Securinine and norsecurinine analogue compounds for the treatment of myeloid disorders

ABSTRACT

The present application relates to securinine or norsecurinine analogues that, when administered to immature myeloid cells, promote differentiation of these cells to mature cells that do not readily proliferate. Therefore, the agents are useful in the treatment of myeloid disorders including myeloproliferative disorders, acute myeloid leukemia, and autoimmune diseases. The agents may also be used as a myeloablative agent in conjunction with a bone marrow transplant or stem cell therapy.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. provisionalapplication 61/886,448, filed Oct. 3, 2013, and to U.S. provisionalapplication 62/051,595, filed Sep. 17, 2014, each of which is herebyincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Acute Myeloid Leukemia (AML) is one of the most common forms of leukemiain adults and despite advances in treatment, the 5 year survival isstill less than 50% in adults and significantly lower in the elderly. Infact, the median survival in patients over the age of 56 is less thanone year and only 20% of these patients survive two years. Though theprognosis for younger patients is significantly better, disease-freesurvival at 6 years following complete remission is still only 40% inchildren and young adults. There is an enormous unmet need for noveltherapeutics to improve the morbidity and mortality of these patients,and for patients suffering from other myeloid disorders. This unmet needis particularly high in the elderly who often cannot toleratetraditional chemotherapy due to toxicities. Though there have been anumber of clinical trials, there has been little improvement in overallsurvival in this age group over the last 30 years.

Acute myeloid leukemia is a broad range of disorders that are allcharacterized by leukemic cells that have a differentiation arrest. AMLcan be classified morphologically according to theFrench-American-British criteria by the degree of differentiation aswell as extent of cell maturation as M0-M7. Treatment for all subtypesof AML is very similar, except for acute promyelocytic leukemia (APL, M3subtype). Traditional therapy involves combination systemicchemotherapy. Several different approaches are utilized. However, theseapproaches usually involve an induction therapy with cytarabine and asecond chemotherapeutic such as daunorubicin or idarubicin andconsolidation therapy with either a bone marrow transplant or additionalchemotherapy. Besides significant side effects from the traditionalchemotherapeutics, the efficacy of these agents in treating AML is poor.

To date the only exception to the poor treatment options for AML is theremarkable success of all-trans-retinoic acid (ATRA) for one relativelyuncommon AML subtype (5-10% of AML), acute promyelocytic leukemia (APL).Utilizing a combination of ATRA and chemotherapy, the long term survivaland presumed cure of 75-85% of patients is possible. ATRA illustratesthe great promise for new agents with greater efficacy and lesstoxicity. In fact, elderly patients with APL who cannot toleratetraditional chemotherapy can achieve complete remission with therapiesthat utilize ATRA.

ATRA's success stems from the fact that AML is a clonal diseasecharacterized by the arrest of differentiation of immature myeloidcells. ATRA overcomes this block in differentiation by forcing leukemiccells to terminally differentiate so that they are no longer capable ofdividing. ATRA is successful in APL due to its ability to reverse thedominant negative effects of the PML-RAR fusion protein created by achromosomal translocation, classically t(15;17)(q22;q21). This fusionprotein interacts with the retinoid x receptor (RXR), nuclearcorepressors and histone deacetylase (HDAC) resulting in repression oftranscription that leads to the block in differentiation. Atpharmacologic doses, ATRA is able to overcome the repression oftranscription and differentiation results. Unfortunately, APL is a raresubtype of AML and ATRA has not been found to be clinically useful forother subtypes. As such, there is a need for compounds that efficientlytreat other subtypes of AML and other myeloid disorders.

Though many compounds have been shown to have somedifferentiation-inducing effects in vitro, their clinical utility hasbeen limited by either suboptimal differentiation-inducing capacityand/or toxicity. For example, Vitamin D3 induces potent differentiation,however, it also causes severe hypercalcemia at the required dose.Treatments that promote the differentiation of immature myeloid cellshold considerable promise in improving the long term survival of AMLpatients while avoiding some of the toxicities of traditionalchemotherapy. Treatment of leukemia could be revolutionized by novelcompounds due to their potential to cure leukemia and provide elderlypatients with alternative nontoxic regimens.

SUMMARY OF THE INVENTION

Embodiments described herein relate to compounds or therapeutic agentsthat can be used to treat myeloid disorders, such as myeloidproliferative disorders (e.g., acute myeloid leukemia). In someembodiments, these compounds can include securinine or norsecurinineanalogues that, when administered to immature myeloid cells of asubject, can promote differentiation of the immature myeloid cells tomore mature cells that do not readily proliferate. The compounds of thedisclosure have a high-potency and low toxicity in mammalian subjectsand can be used in the treatment of myeloid disorders, such asmyeloproliferative disorders, acute myeloid leukemia and autoimmunediseases, and to induce and/or promote differentiation of the myeloidcells. The agents can also be used as a myeloablative agent inconjunction with bone marrow transplantation and stem cell therapies.

One aspect of the present invention provides a method of treating amyeloid disorder in a subject. In some embodiments, the method comprisesadministering to the subject a therapeutically effective amount of atleast one securinine or norsecurinine analogue compound that issufficient to induce differentiation of the cell. In certainembodiments, the securinine or norsecurinine analogue is a compound ofFormula (I), Formula (I′), Formula (II), Formula (III), Formula (IV), orFormula (IV′) or compounds 1-7, 9, 11, 13-73, 75-88, 90-97, or 99-112 orpharmaceutically acceptable salts thereof.

In some embodiments, the securinine or norsecurinine analogue of Formula(I) is selected from the group consisting of compounds 1, 2, 11, 13, or14 or pharmaceutically acceptable salts thereof.

In other embodiments, the securinine or norsecurinine analogue ofFormula (I′) is compound 9 or pharmaceutically acceptable salts thereof.

In certain embodiments, the securinine or norsecurinine analogue ofFormula (II) is selected from the group consisting of compounds 3-7 orpharmaceutically acceptable salts thereof.

In some embodiments, the securinine or norsecurinine analogue of Formula(III) is selected from the group consisting of compounds 15-64 or101-112 or pharmaceutically acceptable salts thereof.

In other embodiments, the securinine or norsecurinine analogue ofFormula (IV) is selected from the group consisting of compounds 65-73,75-88, 90-97, or 99-100 or pharmaceutically acceptable salts thereof.

In certain embodiments, the method of treating a myeloid disorder in asubject comprises administering to the subject a therapeuticallyeffective amount of at least one securinine or norsecurinine analogue ofFormula (I), Formula (I′), Formula (II), Formula (III), Formula (IV), orFormula (IV′) or compounds 1-7, 9, 11, 13-73, 75-88, 90-97, or 99-112 orpharmaceutically acceptable salts thereof and an anti-proliferativeagent in combination with the securinine or norsecurinine analogue. Inother embodiments, the anti-proliferative agent is an anti-metaboliteand/or a nucleoside analogue, an alkylating agent, an antibiotic-typeagent, a hormonal anticancer agent, an immunological agent, aninterferon-type agent, or an antineoplastic agent.

In some embodiments, the subject with a myeloid disorder is a mammal. Incertain embodiments, the mammal is a human.

In certain embodiments, the myeloid disorder is associated withincreased proliferation of cells of the myeloid lineage. In otherembodiments, the myeloid disorder is leukemia. In some embodiments, themyeloid disorder is a sarcoma. In certain embodiments, the increasedproliferation of the cells is reduced following administration of thesecurinine or norsecurinine analogue.

In other embodiments, the myeloid disorder is associated with reduceddifferentiation and/or survival of a myeloid cell or a cell of myeloidlineage. In some embodiments, the myeloid disorder is associated withreduced hematopoiesis of cells of the myeloid lineage. In certainembodiments, the myeloid disorder is an autoimmune disease.

In some embodiments, the myeloid disorder is selected from the groupconsisting of: acute myeloid leukemia (AML), chronic myeloid leukemia(CML), myelodysplastic syndromes (MDS), myelodysplasia, MyelodysplasticSyndrome (e.g., refractory anemia (RA), refractory anemia with ringsideroblasts (RARS), refractory anemia with excess blasts (RAEB),refractory anemia with excess blasts in transformation (RAEBT), and/orchronic myelomonocytic leukemia (CMMoL)), myeloid sarcoma, chloroma,chronic myeloproliferative diseases (CMPD), essential thrombocythemia,polycythemia vera, chronic myelogenous leukemia, myelofibrosis,myelofibrosis with myeloid metaplasia (MMM—also known as agnogenicmyeloid metaplasia or idiopathic myelofibrosis), atypical CMD, chronicneutrophilic leukemia, chronic eosinophilic leukemia, systemicmastocytosis, mast cell disease, chronic neutrophilic leukemia (CNL),chronic eosinophilic leukemia (CEL), hypereosinophilic syndrome (HES),unclassified MPD (UMPD), chronic myelomonocytic leukemia (CMML),juvenile myelomonocytic leukemia (JMML), Down Syndrome related myeloiddisorders, and myeloid processes that display overlapping features ofMDS and CMPD (hybrid CMD).

In certain embodiments, the subject having the myeloid disorder has amutation in one or more of the following genes: JAK2, NPM1, MPL, RAS,RUNX1, ASXL1, BCORL1, CBL, DNMT3A, EZH2, IDH1/IDH2, TET2, UTX, SF3B1,SRSF2, U2AF35/U2AF1, ZRSR2, PTPN11, SH3KBP1, CDKN2A/B, TRIM33, CTNNA1,SOCS1 and/or SF3B1.

Another aspect of the invention provides a method of inducingdifferentiation of a cell of the myeloid lineage. In some embodiments,the method comprises administering to the cell an amount of at least onesecurinine or norsecurinine analogue compound. In certain embodiments,the securinine or norsecurinine analogue is a compound of Formula (I),Formula (I′), Formula (II), Formula (III), Formula (IV), or Formula(IV′) or compounds 1-7, 9, 11, 13-73, 75-88, 90-97, or 99-112 orpharmaceutically acceptable salts thereof.

In some embodiments, the securinine or norsecurinine analogue of Formula(I) is selected from the group consisting of compounds 1, 2, 11, 13, or14 or pharmaceutically acceptable salts thereof.

In other embodiments, the securinine or norsecurinine analogue ofFormula (I′) is compound 9 or pharmaceutically acceptable salts thereof.

In certain embodiments, the securinine or norsecurinine analogue ofFormula (II) is selected from the group consisting of compounds 3-7 orpharmaceutically acceptable salts thereof.

In some embodiments, the securinine or norsecurinine analogue of Formula(III) is selected from the group consisting of compounds 15-64 or101-112 or pharmaceutically acceptable salts thereof.

In other embodiments, the securinine or norsecurinine analogue ofFormula (IV) is selected from the group consisting of compounds 65-73,75-88, 90-97, or 99-100 or pharmaceutically acceptable salts thereof.

In certain embodiments, the method of inducing differentiation of a cellof the myeloid lineage comprises administering to the subject atherapeutically effective amount of at least one securinine ornorsecurinine analogue of Formula (I), Formula (I′), Formula (II),Formula (III), Formula (IV), or Formula (IV′) or compounds 1-7, 9, 11,13-73, 75-88, 90-97, or 99-112 or pharmaceutically acceptable saltsthereof and an anti-proliferative agent in combination with thesecurinine or norsecurinine analogue. In other embodiments, theanti-proliferative agent is an anti-metabolite and/or a nucleosideanalogue, an alkylating agent, an antibiotic-type agent, a hormonalanticancer agent, an immunological agent, an interferon-type agent, oran antineoplastic agent.

In certain embodiments, the cell of the myeloid lineage is in a subject.In some embodiments, the subject is a mammal. In certain embodiments,the mammal is a human.

In other embodiments, the cell is a common myeloid progenitor cell,myeloblast, megakaryoblast, proerythroblast, monoblast,promegakaryocyte, megakaryocyte, basophilic erythroblast, polychromaticerythroblast, orthochromatic erythroblast (normoblast), polychromaticerythrocyte, promonocyte, monocyte, or any one of abasophilic/neutrophilic/eosinophilic precursor cells.

In certain embodiments, the cell of the myeloid lineage is a cancercell. In some embodiments, the cancer cell is a leukemic cell or sarcomacell.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In order that the invention described herein may be fully understood,the following detailed description is set forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art to which this invention belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. The materials, methods and examples areillustrative only, and are not intended to be limiting. Allpublications, patents and other documents mentioned herein areincorporated by reference in their entirety.

Each embodiment of the invention described herein may be taken alone orin combination with one or more other embodiments of the invention.

Throughout this specification, the word “a” will be understood to implythe inclusion of one or more of the integers modified by the article“a.”

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer or groups of integers but not the exclusion of anyother integer or group of integers.

The term “or” as used herein should be understood to mean “and/or”,unless the context clearly indicates otherwise.

“Myeloid disorder” means any disease, disorder or condition associatedwith aberrant proliferation, differentiation and/or survival of a cellof the myeloid lineage (e.g., a common myeloid progenitor cell). In someembodiments, the myeloid disorder is associated with increasedproliferation of a cell of the myeloid lineage (e.g., myeloid leukemia).In some embodiments, the myeloid disorder is associated with reduceddifferentiation and/or survival of a myeloid cell or a cell of myeloidlineage. In some embodiments, the myeloid disorder is associated withreduced hematopoiesis of cells of the myeloid lineage. In someembodiments, the myeloid disorder is an autoimmune disease. Examples ofmyeloid disorders include, but are not limited to, any one of: acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplasticsyndromes (MDS), myelodysplasia, Myelodysplastic Syndrome (e.g.,refractory anemia (RA), refractory anemia with ring sideroblasts (RARS),refractory anemia with excess blasts (RAEB), refractory anemia withexcess blasts in transformation (RAEBT), and/or chronic myelomonocyticleukemia (CMMoL)), myeloid sarcoma, chloroma, chronic myeloproliferativediseases (CMPD), essential thrombocythemia, polycythemia vera, chronicmyelogenous leukemia, myelofibrosis, myelofibrosis with myeloidmetaplasia (MMM—also known as agnogenic myeloid metaplasia or idiopathicmyelofibrosis), atypical CMD, chronic neutrophilic leukemia, chroniceosinophilic leukemia, systemic mastocytosis, mast cell disease, chronicneutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL),hypereosinophilic syndrome (HES), unclassified MPD (UMPD), chronicmyelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML),Down Syndrome related myeloid disorders, and myeloid processes thatdisplay overlapping features of MDS and CMPD (hybrid CMD). In someembodiments, a subject having a myeloid disorder has a mutation in oneor more of the following genes: JAK2, NPM1, MPL, RAS, RUNX1, ASXL1,BCORL1, CBL, DNMT3A, EZH2, IDH1/IDH2, TET2, UTX, SF3B1, SRSF2,U2AF35/U2AF1, ZRSR2, PTPN11, SH3KBP1, CDKN2A/B, TRIM33, CTNNA1, SOCS1and/or SF3B1. In some embodiments, a myeloid disorder is any of themyeloid disorders described in Murati et al., 2012, BMC Cancer, 12:304.

A cell of the myeloid lineage includes common myeloid progenitor cellsand any cell derived from a common myeloid progenitor cell. In someembodiments, a cell of the myeloid lineage is one or more of thefollowing: a common myeloid progenitor cell, megakaryoblast,promegakaryocyte, megakaryocyte, proerythroblast (pronormoblast),basophilic erythroblast, polychromatic erythroblast, orthochromaticerythroblast (normoblast), polychromatic erythrocyte (reticulocyte),monoblast, promonocyte, monocyte, or any basophil/neutrophil/eosinophilprecursor cells (e.g., promyelocyte, myelocyte, metamyelocyte or band).In some embodiments, a cell of the myeloid lineage is selected from thegroup consisting of: a thrombocyte, erythrocyte, mast cell, basophil,neutrophil, eosinophil, macrophage, and myeloid dendritic cell. In someembodiments, a cell of the myeloid lineage is a tumor cell. In someembodiments, a cell of the myeloid lineage is a cancer cell. In someembodiments, the cell of the myeloid lineage is a leukemic cell. In someembodiments, the cell is a myeloid sarcoma cell.

The term “securinine” refers to the compound(6S,11aR,11bS)-9,10,11,11a-tetrahydro-8H-6,11b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one,with a molecular formula of C₁₃H₁₅NO₂, a molecular weight of 217.2637,and a CAS Registry Number of 5610-40-2.

The term “norsecurinine” refers to the compound ((6S,10aR,10bS)-8,9,10,10a-tetrahydro-6,10b-methanofuro[2,3-c]pyrrolo[1,2-a]azepin-2(6H)-one,with a molecular formula of C₁₂H₁₃NO₂, a molecular weight of 203.2371,and a CAS Registry Number of 2650-35-3.

The terms “securinine analogues” or “norsecurinine analogues” refer tochemical compounds that are structurally similar to securinine ornorsecurinine but differ slightly in composition (as in the replacementof one atom by an atom of a different element or in the presence of aparticular functional group, or the replacement of one functional groupby another functional group). Thus, a securinine analogue or anorsecurinine analogue is a compound that is similar or comparable infunction and appearance to securinine or nonsecurinine, but not instructure or origin to the reference compound. The term “securinineanalogue” can include analogues of norsecurinine.

It will be noted that the structure of some of the compounds of theapplication include asymmetric (chiral) carbon or sulfur atoms. It is tobe understood accordingly that the isomers arising from such asymmetryare included herein, unless indicated otherwise. Such isomers can beobtained in substantially pure form by classical separation techniquesand by stereochemically controlled synthesis. The compounds of thisapplication may exist in stereoisomeric form, and therefore can beproduced as individual stereoisomers or as mixtures. Compounds of thepresent application containing one or multiple asymmetricallysubstituted atoms may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms, by synthesis from optically activestarting materials, or by synthesis using optically active reagents.

In certain embodiments, compounds of the application may be racemic. Incertain embodiments, compounds of the application may be enriched in oneenantiomer. For example, a compound of the application may have greaterthan 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95%or greater ee.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one enantiomer of a compound (e.g., of formula (I)or (II)). An enantiomerically enriched mixture may comprise, forexample, at least 60 mol percent of one enantiomer, or more preferablyat least 75, 90, 95, or even 99 mol percent. In certain embodiments, thecompound enriched in one enantiomer is substantially free of the otherenantiomer, wherein substantially free means that the substance inquestion makes up less than 10%, or less than 5%, or less than 4%, orless than 3%, or less than 2%, or less than 1% as compared to the amountof the other enantiomer, e.g., in the composition or compound mixture.For example, if a composition or compound mixture contains 98 grams of afirst enantiomer and 2 grams of a second enantiomer, it would be said tocontain 98 mol percent of the first enantiomer and only 2% of the secondenantiomer.

In certain embodiments, compounds of the application may have more thanone stereocenter. In certain such embodiments, compounds of theapplication may be enriched in one or more diastereomer. For example, acompound of the application may have greater than 30% de, 40% de, 50%de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one diastereomer of a compound (e.g., of Formula(I) or (II)). A diastereomerically enriched mixture may comprise, forexample, at least 60 mol percent of one diastereomer, or more preferablyat least 75, 90, 95, or even 99 mol percent.

The term “isomerism” means compounds that have identical molecularformulae but that differ in the nature or the sequence of bonding oftheir atoms or in the arrangement of their atoms in space. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. Stereoisomers that are not mirror images of one anotherare termed “diastereoisomers”, and stereoisomers that arenon-superimposable mirror images are termed “enantiomers”, or sometimesoptical isomers. A carbon atom bonded to four nonidentical substituentsis termed a “chiral center” whereas a sulfur bound to three or fourdifferent substitutents, e.g. sulfoxides or sulfinimides, is likewisetermed a “chiral center”.

The term “chiral isomer” means a compound with at least one chiralcenter. It has two enantiomeric forms of opposite chirality and mayexist either as an individual enantiomer or as a mixture of enantiomers.A mixture containing equal amounts of individual enantiomeric forms ofopposite chirality is termed a “racemic mixture”. A compound that hasmore than one chiral center has 2n−1 enantiomeric pairs, where n is thenumber of chiral centers. Compounds with more than one chiral center mayexist as either an individual diastereomer or as a mixture ofdiastereomers, termed a “diastereomeric mixture”. When one chiral centeris present, a stereoisomer may be characterized by the absoluteconfiguration (R or S) of that chiral center. Alternatively, when one ormore chiral centers are present, a stereoisomer may be characterized as(+) or (−). Absolute configuration refers to the arrangement in space ofthe substituents attached to the chiral center. The substituentsattached to the chiral center under consideration are ranked inaccordance with the Sequence Rule of Cahn, Ingold and Prelog (Cahn etal., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al.,Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem.Educ. 1964, 41, 116).

The term “geometric isomers” means the diastereomers that owe theirexistence to hindered rotation about double bonds. These configurationsare differentiated in their names by the prefixes cis and trans, or Zand E, which indicate that the groups are on the same or opposite sideof the double bond in the molecule according to the Cahn-Ingold-Prelogrules. Further, the structures and other compounds discussed in thisapplication include all atropic and geometric isomers thereof.

The term “atropic isomers” are a type of stereoisomer in which the atomsof two isomers are arranged differently in space. Atropic isomers owetheir existence to a restricted rotation caused by hindrance of rotationof large groups about a central bond. Such atropic isomers typicallyexist as a mixture, however as a result of recent advances inchromatography techniques, it has been possible to separate mixtures oftwo atropic isomers in select cases.

The terms “crystal polymorphs” or “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or salt or solvate thereof) cancrystallize in different crystal packing arrangements, all of which havethe same elemental composition. Different crystal forms usually havedifferent X-ray diffraction patterns, infrared spectral, melting points,density hardness, crystal shape, optical and electrical properties,stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

The term “derivative” refers to compounds that have a common corestructure, and are substituted with various groups as described herein.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres includeacyl sulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g.,Patani and LaVoie, Chem. Rev. 1996, 96, 3147-3176.

The compounds of the application are capable of further forming salts.All of these forms are also contemplated herein.

“Pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. For example, the saltcan be an acid addition salt. One embodiment of an acid addition salt isa hydrochloride salt. The pharmaceutically acceptable salts can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.Lists of salts are found in Remington's Pharmaceutical Sciences, 18thed. (Mack Publishing Company, 1990). In certain embodiments,contemplated salts of the compounds include, but are not limited to,alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certainembodiments, contemplated salts of compounds include, but are notlimited to, L-arginine, benenthamine, benzathine, betaine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)ethanol, ethanolamine, ethylenediamine,N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine,magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium,1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, trimethamine,and zinc salts. In certain embodiments, contemplated salts of compoundsinclude, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

The compounds described herein can also be prepared as esters, forexample pharmaceutically acceptable esters. For example, a carboxylicacid function group in a compound can be converted to its correspondingester, e.g., a methyl, ethyl, or other ester. Also, an alcohol group ina compound can be converted to its corresponding ester, e.g., anacetate, propionate, or other ester.

The compounds described herein can also be prepared as prodrugs, forexample pharmaceutically acceptable prodrugs. The terms “pro-drug” and“prodrug” are used interchangeably herein and refer to any compound,which releases an active parent drug in vivo. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds can bedelivered in prodrug form. Thus, the compounds described herein areintended to cover prodrugs of the presently claimed compounds, methodsof delivering the same and compositions containing the same. “Prodrugs”are intended to include any covalently bonded carriers that release anactive parent drug in vivo when such prodrug is administered to asubject. Prodrugs are prepared by modifying functional groups present inthe compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds wherein a hydroxy, amino, sulfhydryl, carboxy, orcarbonyl group is bonded to any group that may be cleaved in vivo toform a free hydroxyl, free amino, free sulfhydryl, free carboxy or freecarbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates, andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, ester groups (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl)N-Mannich bases, Schiff bases and enaminonesof amino functional groups, oximes, acetals, ketals and enol esters ofketone and aldehyde functional groups, and the like, See Bundegaard, H.“Design of Prodrugs” p 1-92, Elesevier, New York-Oxford (1985).

Additionally, the salts of the compounds described herein, can exist ineither hydrated or unhydrated (the anhydrous) form or as solvates withother solvent molecules. Nonlimiting examples of hydrates includemonohydrates, dihydrates, etc. Nonlimiting examples of solvates includeethanol solvates, acetone solvates, etc.

The term “solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

The compounds, salts and prodrugs described herein can exist in severaltautomeric forms, including the enol and imine form, and the keto andenamine form and geometric isomers and mixtures thereof. Tautomers existas mixtures of a tautomeric set in solution. In solid form, usually onetautomer predominates. Even though one tautomer may be described, thepresent application includes all tautomers of the present compounds. Atautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Insolutions where tautomerization is possible, a chemical equilibrium ofthe tautomers will be reached. The exact ratio of the tautomers dependson several factors, including temperature, solvent, and pH. The conceptof tautomers that are interconvertable by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Tautomerizations can be catalyzed by: Base: 1.deprotonation; 2. formation of a delocalized anion (e.g., an enolate);3. protonation at a different position of the anion; Acid: 1.protonation; 2. formation of a delocalized cation; 3. deprotonation at adifferent position adjacent to the cation.

The term “analogue” refers to a chemical compound that is structurallysimilar to another but differs slightly in composition (as in thereplacement of one atom by an atom of a different element or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analogue is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

With respect to any chemical compounds, the present application isintended to include all isotopes of atoms occurring in the presentcompounds. Isotopes include those atoms having the same atomic numberbut different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include C-13 and C-14.

The term “protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in Green andWuts, Protective Groups in Organic Chemistry, (Wiley, 2.sup.nd ed.1991); Harrison and Harrison et al., Compendium of Synthetic OrganicMethods, Vols. 1-8 (John Wiley and Sons, 1971-1996); and Kocienski,Protecting Groups, (Verlag, 3^(rd) ed. 2003).

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When an atom or a chemical moiety is followed by a subscripted numericrange (e.g., C₁₋₆), it is meant to encompass each number within therange as well as all intermediate ranges. For example, “C₁₋₆ alkyl” ismeant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3,1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. Exemplaryaralkyl groups contain 6 to 24 carbon atoms, and in some embodiments,aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groupsinclude, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl,4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl,4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl,p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl,3-ethyl-cyclopenta-1,4-diene, and the like.

The term “alkyl” refers to a linear, branched or cyclic hydrocarbongroup of 1 to about 24 carbon atoms is intended to include both branched(e.g., isopropyl, tert-butyl, isobutyl), straight-chain e.g., methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), andcycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. Such aliphatichydrocarbon groups have a specified number of carbon atoms. For example,C₁₋₆ alkyl is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkylgroups. As used herein, “lower alkyl” refers to alkyl groups having from1 to 6 carbon atoms in the backbone of the carbon chain. “Alkyl” furtherincludes alkyl groups that have oxygen, nitrogen, sulfur or phosphorousatoms replacing one or more hydrocarbon backbone carbon atoms. Incertain embodiments, a straight chain or branched chain alkyl has six orfewer carbon atoms in its backbone (e.g., C₁-C₆ for straight chain,C₃-C₆ for branched chain), for example four or fewer. Likewise, certaincycloalkyls have from three to eight carbon atoms in their ringstructure, such as five or six carbons in the ring structure.

The term “substituted alkyl” refers to alkyl moieties havingsubstituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “alkylaryl” or an “aralkyl” or a “heteroaralkyl”moiety is an alkyl substituted with an aryl or heteroaryl group (e.g.,phenylmethyl (benzyl)). If not otherwise indicated, the terms “alkyl”and “lower alkyl” include linear, branched, cyclic, unsubstituted,substituted, and/or heteroatom-containing alkyl or lower alkyl,respectively.

The term “alkenyl” refers to a linear, branched or cyclic hydrocarbongroup of 2 to about 24 carbon atoms containing at least one double bond,such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl,octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl,cyclopentenyl, cyclohexenyl, cyclooctenyl, and the like. Generally,although again not necessarily, alkenyl groups can contain 2 to about 18carbon atoms, and more particularly 2 to 12 carbon atoms. The term“lower alkenyl” refers to an alkenyl group of 2 to 6 carbon atoms, andthe specific term “cycloalkenyl” intends a cyclic alkenyl group, orhaving 5 to 8 carbon atoms.

The term “substituted alkenyl” refers to alkenyl substituted with one ormore substituent groups, and the terms “heteroatom-containing alkenyl”and “heteroalkenyl” refer to alkenyl or heterocycloalkenyl (e.g.,heterocylcohexenyl) in which at least one carbon atom is replaced with aheteroatom. If not otherwise indicated, the terms “alkenyl” and “loweralkenyl” include linear, branched, cyclic, unsubstituted, substituted,and/or heteroatom-containing alkenyl and lower alkenyl, respectively.

The term “alkynyl” refers to a linear or branched hydrocarbon group of 2to 24 carbon atoms containing at least one triple bond, such as ethynyl,n-propynyl, and the like. Generally, although again not necessarily,alkynyl groups can contain 2 to about 18 carbon atoms, and moreparticularly can contain 2 to 12 carbon atoms. The term “lower alkynyl”intends an alkynyl group of 2 to 6 carbon atoms. The term “substitutedalkynyl” refers to alkynyl substituted with one or more substituentgroups, and the terms “heteroatom-containing alkynyl” and“heteroalkynyl” refer to alkynyl in which at least one carbon atom isreplaced with a heteroatom. If not otherwise indicated, the terms“alkynyl” and “lower alkynyl” include linear, branched, unsubstituted,substituted, and/or heteroatom-containing alkynyl and lower alkynyl,respectively.

The terms “alkyl”, “alkenyl”, and “alkynyl” are intended to includemoieties which are diradicals, i.e., having two points of attachment. Anonlimiting example of such an alkyl moiety that is a diradical is—CH₂CH₂—, i.e., a C₂ alkyl group that is covalently bonded via eachterminal carbon atom to the remainder of the molecule.

The term “alkoxy” refers to an alkyl group bound through a single,terminal ether linkage; that is, an “alkoxy” group may be represented as—O-alkyl where alkyl is as defined above. A “lower alkoxy” group intendsan alkoxy group containing 1 to 6 carbon atoms, and includes, forexample, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc. Insome embodiments, substituents identified as “C₁-C₆ alkoxy” or “loweralkoxy” herein contain 1 to 3 carbon atoms, and in particularembodiments, such substituents contain 1 or 2 carbon atoms (i.e.,methoxy and ethoxy).

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The terms “alkylthio” or “alkylsulfanyl” as used herein, refer to athiol group substituted with an alkyl group and may be represented bythe general formula alkylS—.

The term “amide”, as used herein, refers to a group

wherein each R₁ independently represent a hydrogen or hydrocarbyl group,or two R₁ are taken together with the N atom to which they are attachedcomplete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R₁ independently represents a hydrogen or a hydrocarbylgroup, or two R₁ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aryl” refers to an aromatic substituent containing a singlearomatic ring or multiple aromatic rings that are fused together,directly linked, or indirectly linked (such that the different aromaticrings are bound to a common group such as a methylene or ethylenemoiety). Aryl groups can contain 5 to 20 carbon atoms, and in someembodiments, aryl groups can contain 5 to 14 carbon atoms. Examples ofaryl groups include benzene, phenyl, pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, andthe like. Furthermore, the term “aryl” includes multicyclic aryl groups,e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole,benzodioxazole, benzothiazole, benzoimidazole, benzothiophene,methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,benzofuran, purine, benzofuran, deazapurine, or indolizine. Those arylgroups having heteroatoms in the ring structure may also be referred toas “aryl heterocycles”, “heterocycles,” “heteroaryls” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, as forexample, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diaryl amino, and alkylaryl amino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclicrings, which are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl). If not otherwise indicated, the term“aryl” includes unsubstituted, substituted, and/or heteroatom-containingaromatic substituents.

The term “azido” is art-recognized and refers to the group —N═N⁺N⁻.

The term “carbamate” is art-recognized and refers to a group

wherein R₁ and R₂ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R₁ and R₂ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The term carbamoyl is art-recognized and refers to the group representedby —(CO)—NH₂.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “cycloalkyl alkyl”, as used herein, refers to an alkyl groupsubstituted with a cycloalkyl group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R₁,wherein R₁ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “cyano” is art-recognized and refers to the group —CN.

The term “cyanato” is art-recognized and refers to the group —O—CN.

The term “ester”, as used herein, refers to a group —C(O)OR₁ wherein R₁represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The term “formyl” is art-recognized and refers the group —(CO)—H.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The terms “heterocyclyl” or “heterocyclic group” include closed ringstructures, e.g., 3- to 10-, or 4- to 7-membered rings, which includeone or more heteroatoms. “Heteroatom” includes atoms of any elementother than carbon or hydrogen. Examples of heteroatoms include nitrogen,oxygen, sulfur and phosphorus.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

Heterocyclyl groups can be saturated or unsaturated and includepyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine,lactones, lactams, such as azetidinones and pyrrolidinones, sultams, andsultones. Heterocyclic groups such as pyrrole and furan can havearomatic character. They include fused ring structures, such asquinoline and isoquinoline. Other examples of heterocyclic groupsinclude pyridine and purine. The heterocyclic ring can be substituted atone or more positions with such substituents as described above, as forexample, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, thiocarboxylate, sulfates, sulfonato,sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, or an aromatic or heteroaromatic moiety. Heterocyclicgroups can also be substituted at one or more constituent atoms with,for example, a lower alkyl, a lower alkenyl, a lower alkoxy, a loweralkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, ahydroxyl, —CF₃, or —CN, or the like.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.“Counterion” is used to represent a small, negatively charged speciessuch as fluoride, chloride, bromide, iodide, hydroxide, acetate, andsulfate.

The term “imino” is art-recognized and refers to the group representedby —CR₁═NH, wherein R₁ is selected from the group comprising hydrogen orhydrocarbyl.

The term “isocyanato” is art-recognized and refers to the group—O—N⁺═C⁻.

The term “isocyano” is art-recognized and refers to the group —N⁺ C⁻.

The term “isothiocyanato” is art-recognized and refers to the group—S—CN.

The term “nitro” is art-recognized and refers to the group representedby —NO₂.

The term “nitroso” is art-recognized and refers to the group representedby —NO.

The term “phosphono” is art-recognized and refers to the grouprepresented by —P(O)(OH)₂.

The term “phosphonato” is art-recognized and refers to the grouprepresented by —P(O)(O⁻)₂.

The term “phosphinato” is art-recognized and refers to the grouprepresented by —P(O)(O⁻)₂.

The term “phospho” is art-recognized and refers to the group representedby —PO₂.

The term “phosphino” is art-recognized and refers to the grouprepresented by —PH₂.

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto.

The terms “substituted” as in “substituted alkyl,” “substituted aryl,”and the like, as alluded to in some of the aforementioned definitions,is meant that in the alkyl, aryl, or other moiety, at least one hydrogenatom bound to a carbon (or other) atom is replaced with one or morenon-hydrogen substituents. Examples of such substituents include,without limitation: functional groups such as alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, heterocyclyl, alkaryl, aralkyl, halo,hydroxyl, silyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy,acyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonato,arylcarbonato, carboxy, carboxylato, carbamoyl, thiocarbamoyl,carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido,formyl, thioformyl, amino, alkylamido, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, and phosphino.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R₁ and R₂ independently represents hydrogen or hydrocarbyl, suchas alkyl, or R₁ and R₂ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms “sulfoxide” or “alkylsulfinyl” are art-recognized and refer tothe group —S(O)—R₁, wherein R₁ represents a hydrocarbyl.

The terms “sulfonate” or “sulfo” are art-recognized and refer to thegroup SO₃H, or a pharmaceutically acceptable salt thereof.

The terms “sulfone” or “alkylsulfonyl” are art-recognized and refer tothe group —S(O)₂—R₁, wherein R₁ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thiocarbamoyl” is art-recognized and refers to the group—(CS)—NH₂.

The term “thioester”, as used herein, refers to a group —C(O)SR₁ or—SC(O)R₁ wherein R₁ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with asulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R₁ and R₂ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R₁ taken together with R₂ and theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

In addition, the aforementioned functional groups may, if a particulargroup permits, be further substituted with one or more additionalfunctional groups or with one or more hydrocarbyl moieties such as thosespecifically enumerated above. Analogously, the above-mentionedhydrocarbyl moieties may be further substituted with one or morefunctional groups or additional hydrocarbyl moieties such as thosespecifically enumerated.

When the term “substituted” appears prior to a list of possiblesubstituted groups, it is intended that the term apply to every memberof that group. For example, the phrase “substituted alkyl, alkenyl, andaryl” is to be interpreted as “substituted alkyl, substituted alkenyl,and substituted aryl.” Analogously, when the term“heteroatom-containing” appears prior to a list of possibleheteroatom-containing groups, it is intended that the term apply toevery member of that group. For example, the phrase“heteroatom-containing alkyl, alkenyl, and aryl” is to be interpreted as“heteroatom-containing alkyl, substituted alkenyl, and substituted aryl.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.For example, the phrase “optionally substituted” means that anon-hydrogen substituent may or may not be present on a given atom, and,thus, the description includes structures wherein a non-hydrogensubstituent is present and structures wherein a non-hydrogen substituentis not present.

The term “stability,” “stable,” “stable compound,” or “stable structure”in the context of a chemical structure refers to the chemical state whena system is in its lowest energy state, or in chemical equilibrium withits environment. Thus, a stable compound (or, e.g., a compoundcontaining a number of atoms or substitutions that are stable) is notparticularly reactive in the environment or during normal use, andretains its useful properties on the timescale of its expectedusefulness. A stable compound is sufficiently robust to surviveisolation, and as appropriate, purification from a reaction mixture, andformulation into an efficacious therapeutic agent.

The terms “free compound” is used herein to describe a compound in theunbound state.

Throughout the description, where compositions are described as having,including, or comprising, specific components, it is contemplated thatcompositions also may consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso may consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the compositionsand methods described herein remains operable. Moreover, two or moresteps or actions can be conducted simultaneously.

The term “small molecule” is an art-recognized term. In certainembodiments, this term refers to a molecule, which has a molecularweight of less than about 2000 amu, or less than about 1000 amu, andeven less than about 500 amu.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

The term “ED50” is art-recognized. In certain embodiments, ED50 meansthe dose of a drug, which produces 50% of its maximum response oreffect, or alternatively, the dose, which produces a pre-determinedresponse in 50% of test subjects or preparations. The term “LD50” isart-recognized. In certain embodiments, LD50 means the dose of a drug,which is lethal in 50% of test subjects. The term “therapeutic index” isan art-recognized term, which refers to the therapeutic index of a drug,defined as LD50/ED50.

The terms “IC₅₀,” or “half maximal inhibitory concentration” is intendedto refer to the concentration of a substance (e.g., a compound or adrug) that is required for 50% inhibition of a biological process, orcomponent of a process, including a protein, subunit, organelle,ribonucleoprotein, etc.

The terms “healthy” and “normal” are used interchangeably herein torefer to a subject or particular cell or tissue that is devoid (at leastto the limit of detection) of a disease condition.

Securinine and Norsecurinine Analogues

Embodiments described herein relate to compounds or therapeutic agentsthat, in some embodiments, can be used to induce and/or promotedifferentiation of immature myeloid cells as well as to methods andassays of identifying therapeutic agents or compounds capable ofinducing differentiation of immature myeloid cells. Agents in accordancewith the invention have a high-potency and low toxicity in mammaliansubjects and can be used in the treatment of myeloid disorders, such asmyeloproliferative disorders, acute myeloid leukemia and auto immunedisease. The agents can also be used as a myeloablative agent inconjunction with bone marrow transplantation and stem cell therapies.

The agents in accordance with the present invention can be used alone orin combination with other differentiation inducing agents,anti-proliferative agents, and/or chemotherapeutic agents for thetreatment of proliferative and/or other neoplastic disorders.

In some embodiments, the securinine analogue and norsecurinine analoguecompounds can include compounds that when administered to immaturemyeloid cells of a subject can promote differentiation of the immaturemyeloid cells to more mature cells that do not readily proliferate. Thesecurinine and norsecurinine analogues can be identified using thenitroblue tetrazolium (NBT) reduction assay described herein.

In some embodiments, the securinine and norsecurinine analogues arerepresented by general Formula (I):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

-   represents a single or double bond;-   x is 0 or 1;-   R₁ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl;-   R₂, R₃, R₄, and R₅ are each independently hydrogen or substituted or    unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,    heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl,    aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy,    alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,    alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,    alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,    isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,    thioformyl, amino, alkylamino, arylamino, cycloalkylamino,    heterocyclylamino, cycloalkylalkylamino, arylalkylamino,    heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,    sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,    heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,    arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl,    arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato,    phosphinato, phospho, phosphino, thioalkyl, or thioaryl; and-   wherein adjacent R groups may be linked to form a cyclic or    polycyclic ring, wherein the ring is a substituted or unsubstituted    aryl, a substituted or unsubstituted heteroaryl, a substituted or    unsubstituted cycloalkyl, or a substituted or unsubstituted    heterocyclyl.

In certain embodiments,

represents a double bond.

In certain embodiments when x is 1 and

represents a double bond, at least one of R₁, R₂, R₃, R₄, and R₅ isother than hydrogen.

In certain embodiments, R₁ is hydrogen, halogen, or optionallysubstituted alkyl, aryl, alkenyl, or alkynyl and

represents a double bond.

In certain embodiments, x is 0 and

represents a double bond. In certain such embodiments, R₅ isalkoxyalkyl. In certain such embodiments, R₂ and R₃ are hydrogen.

In certain embodiments, x is 0, R₅ is alkoxyalkyl, R₂ and R₃ arehydrogen, R₁ is optionally substituted alkenyl, and

represents a double bond. In certain embodiments, x is 0, R₅ isalkoxyalkyl, R₂ and R₃ are hydrogen, R₁ is optionally substitutedalkynyl, and

represents a double bond.

In certain embodiments, x is 1. In certain embodiments, x is 1 and

represents a double bond. In certain such embodiments, R₂, R₃, R₄, andR₅ are each hydrogen.

In certain embodiments, x is 1, R₁ is optionally substituted alkenyl,R₂, R₃, R₄, and R₅ are each hydrogen, and

represents a double bond. In certain embodiments, x is 1, R₁ isoptionally substituted alkynyl, R₂, R₃, R₄, and R₅ are each hydrogen,and

represents a double bond.

In certain embodiments, the compound of Formula (I) is selected from:

or pharmaceutically acceptable salts thereof. For example, the compoundis selected from compounds 1, 2, 11, 13, or 14 or pharmaceuticallyacceptable salts thereof. In some embodiments, the compound is selectedfrom compounds 11, 13, or 14 or pharmaceutically acceptable saltsthereof. In other embodiments, the compound is selected from compounds 1or 2 or pharmaceutically acceptable salts thereof.

In some embodiments, the securinine and norsecurinine analogues arerepresented by Formula (I′):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

-   represents a single or double bond;-   x is 0 or 1;-   R₁ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl;-   R₂, R₃, R₄, and R₅ are each independently hydrogen or substituted or    unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,    heterocyclyl, cycloalkyl alkyl, heterocyclylalkyl, heteroaralkyl,    aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy,    alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,    alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,    alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,    isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,    thioformyl, amino, alkylamino, arylamino, cycloalkylamino,    heterocyclylamino, cycloalkylalkylamino, arylalkylamino,    heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,    sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,    heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,    arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl,    arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato,    phosphinato, phospho, phosphino, thioalkyl, or thioaryl;-   wherein adjacent R groups may be linked to form a cyclic or    polycyclic ring, wherein the ring is a substituted or unsubstituted    aryl, a substituted or unsubstituted heteroaryl, a substituted or    unsubstituted cycloalkyl, or a substituted or unsubstituted    heterocyclyl; and-   wherein R₆ is C₁-C₆ alkyl.

In certain embodiments,

represents a double bond.

In certain embodiments when x is 1 and

represents a double bond, at least one of R₁, R₂, R₃, R₄, and R₅ isother than hydrogen.

In certain embodiments, R₁ is hydrogen, halogen, or optionallysubstituted alkyl, aryl, alkenyl, or alkynyl and

represents a double bond.

In certain embodiments, x is 0 and

represents a double bond. In certain such embodiments, R₅ isalkoxyalkyl. In certain such embodiments, R₂ and R₃ are hydrogen.

In certain embodiments, x is 0, R₅ is alkoxyalkyl, R₂ and R₃ arehydrogen, R₁ is optionally substituted alkenyl, and

represents a double bond. In certain embodiments, x is 0, R₅ isalkoxyalkyl, R₂ and R₃ are hydrogen, R₁ is optionally substitutedalkynyl, and

represents a double bond.

In certain embodiments, x is 1. In certain embodiments, x is 1 and

represents a double bond. In certain such embodiments, R₂, R₃, R₄, andR₅ are each hydrogen.

In certain embodiments, x is 1, R₁ is optionally substituted alkenyl,R₂, R₃, R₄, and R₅ are each hydrogen, and

represents a double bond. In certain embodiments, x is 1, R₁ isoptionally substituted alkynyl, R₂, R₃, R₄, and R₅ are each hydrogen,and

represents a double bond.

In certain embodiments, the compound of Formula (I′) is selected from:

and pharmaceutically acceptable salts thereof. For example, the compoundis selected from compound 9 or pharmaceutically acceptable saltsthereof.

In some embodiments, the securinine and norsecurinine analogues ofFormula (I) are represented by the general Formula (II):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

-   represents a single or double bond;-   x is 0 or 1;-   R₁ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl; and-   R₂ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl.

In certain embodiments,

represents a double bond

In certain embodiments when x is 1 and

represents a double bond, at least one of R₁ or R₂ is other thanhydrogen.

In certain embodiments x is 1 and

represents a double bond. In certain such embodiments, R₁ is other thanhydrogen and R₂ is hydrogen.

In certain embodiments, x is 0 and

represents a double bond. In certain such embodiments, R₂ isalkoxyalkyl.

In certain embodiments, R₁ is optionally substituted or unsubstitutedalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl orhalogen. In certain such embodiments,

represents a double bond.

In certain embodiments, the compound of Formula (II) is selected from:

and pharmaceutically acceptable salts thereof.

In some embodiments, the securinine and norsecurinine analogues ofFormula (I) and (II) are represented by the general Formula (III):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

-   represents a single or double bond;-   represents a double or triple bond;-   x is 0 or 1;-   R₁ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl; and-   R₂ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl.

In certain embodiments,

represents a double bond. In certain such embodiments,

represents a triple bond.

In certain embodiments,

represents a double bond. In certain such embodiments, the double bondhas a cis configuration.

In certain embodiments,

represents a double bond. In certain such embodiments, the double bondhas a trans configuration.

In certain embodiments, x is 0,

represents a double bond, and

represents a double bond. In certain such embodiments, R₂ isalkoxyalkyl.

In certain embodiments, x is 0,

represents a double bond, and represents a triple bond. In certain suchembodiments, R₂ is alkoxyalkyl.

In certain embodiments, x is 1,

represents a double bond, and represents a double bond. In certain suchembodiments, R₂ is hydrogen.

In certain embodiments, x is 1,

represents a double bond, and represents a triple bond. In certain suchembodiments, R₂ is hydrogen.

In certain embodiments, R₁ is substituted or unsubstituted alkyl,alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, heteroaryl, alkaryl, aralkyl, heteroaralkyl, hydroxyl, alkoxy,alkoxyalkyl, alkoxyalkylsilyl, alkoxyalkenyl, aryloxyalkyl, oraminoalkyl. In certain such embodiments,

represents a double bond.

In certain embodiments, the compound of Formula (III) is selected from:

or pharmaceutically acceptable salts thereof. For example, the compoundis selected from compounds 15-64, 101, 104, 106, or 112 orpharmaceutically acceptable salts thereof. In some embodiments, thecompound is selected from compounds 107 or 108 or pharmaceuticallyacceptable salts thereof. In other embodiments, the compound is selectedfrom compounds 102, 103, 105, 109 or 111 or pharmaceutically acceptablesalts thereof. In certain embodiments, the compound is selected fromcompound 110 or pharmaceutically acceptable salt thereof.

In some embodiments, the securinine analogues are represented by thegeneral Formula (IV):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond;

-   x is 0 or 1; and-   R₁ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl.

In certain embodiments,

represents a single bond. In certain such embodiments, x is 1.

In certain embodiments wherein R₁ is substituted or unsubstitutedheterocyclyl, R₁ is not fluoro-substituted, such as mono-fluorosubstituted pyrrolidine. For example, in certain embodiments wherein R₁is substituted or unsubstituted heterocyclyl, x is 1, and

represents a single bond, R₁ is not fluoro-substituted, such asmono-fluoro substituted pyrrolidine. In certain embodiments wherein R₁is substituted or unsubstituted heteroarylalkylamino, R₁ is notindolealkylamino. For example, in certain embodiments wherein R₁ issubstituted or unsubstituted heteroarylalkylamino, x is 1, and

represents a single bond, R₁ is not indolealkylamino. In certainembodiments wherein R₁ is substituted or unsubstituted arylsulfanyl, R₁is not phenylsulfanyl. For example, in certain embodiments wherein R₁ issubstituted or unsubstituted arylsulfanyl, x is 1, and

represents a single bond, R₁ is not phenylsulfanyl. In certainembodiments wherein R₁ is alkylsulfanyl, R₁ is not lower alkylsulfanyl,such as propylsulfanyl. For example, in certain embodiments wherein R₁is alkylsulfanyl, x is 1, and

represents a single bond, R₁ is not lower alkylsulfanyl, such aspropylsulfanyl. In certain embodiments, R₁ is hydrogen or substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl,hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl,alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy,carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl,carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido,formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino, aminoalkyl,imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl,amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl,alkylsulfinyl, arylsulfinyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphino, thioalkyl, or thioaryl. In certain suchembodiments,

represents a single bond and x is 1.

In certain embodiments, the compound of Formula (IV) is:

or pharmaceutically acceptable salts thereof. For example, the compoundis selected from compounds 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 99, or 100 or pharmaceutically acceptable salts thereof.

In some embodiments, the securinine analogues are represented by thegeneral Formula (IV′):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

-   represents a single or double bond;-   x is 0 or 1;-   R₁ is hydrogen or substituted or unsubstituted alkyl, alkenyl,    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,    cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo,    silyl, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy,    alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl, alkylcarbonato,    arylcarbonato, carboxy, carboxylato, carbamoyl, alkylcarbamoyl,    arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato,    isocyanato, isothiocyanato, azido, formyl, thioformyl, amino,    alkylamino, arylamino, cycloalkylamino, heterocyclylamino,    cycloalkylalkylamino, arylalkylamino, heteroarylalkylamino,    aminoalkyl, imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,    arylsulfanyl, cycloalkylsulfanyl, heterocyclylsulfanyl,    heteroarylsulfanyl, amidoalkylsulfanyl, arylalkysulfanyl,    heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,    arylsulfonyl, phosphono, phosphonato, phosphinato, phospho,    phosphino, thioalkyl, or thioaryl; and wherein R₂ is C₁-C₆ alkyl.

In certain embodiments,

represents a single bond. In certain such embodiments, x is 1.

In certain embodiments wherein R₁ is substituted or unsubstitutedheterocyclyl, R₁ is not fluoro-substituted, such as mono-fluorosubstituted pyrrolidine. For example, in certain embodiments wherein R₁is substituted or unsubstituted heterocyclyl, x is 1, and

represents a single bond, R₁ is not fluoro-substituted, such asmono-fluoro substituted pyrrolidine. In certain embodiments wherein R₁is substituted or unsubstituted heteroarylalkylamino, R₁ is notindolealkylamino. For example, in certain embodiments wherein R₁ issubstituted or unsubstituted heteroarylalkylamino, x is 1, and

represents a single bond, R₁ is not indolealkylamino. In certainembodiments wherein R₁ is substituted or unsubstituted arylsulfanyl, R₁is not phenylsulfanyl. For example, in certain embodiments wherein R₁ issubstituted or unsubstituted arylsulfanyl, x is 1, and

represents a single bond, R₁ is not phenylsulfanyl. In certainembodiments wherein R₁ is alkylsulfanyl, R₁ is not lower alkylsulfanyl,such as propylsulfanyl. For example, in certain embodiments wherein R₁is alkylsulfanyl, x is 1, and

represents a single bond, R₁ is not lower alkylsulfanyl, such aspropylsulfanyl. In certain embodiments, R₁ is hydrogen or substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl,hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl,alkoxyalkenyl, aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy,carboxylato, carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl,carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido,formyl, thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino, aminoalkyl,imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl,amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl,alkylsulfinyl, arylsulfinyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphino, thioalkyl, or thioaryl. In certain suchembodiments,

represents a single bond and x is 1.

Methods of Treatment and Other Methods of Use

For any of the methods described herein, the disclosure contemplates theuse of any of the securinine or norsecurinine analogue compounds and/orcompositions described throughout the application. In addition, for anyof the methods described herein, the disclosure contemplates thecombination of any step or steps of one method with any step or stepsfrom another method.

In some embodiments, the disclosure provides for a method of inducingdifferentiation of a stem cell. In some embodiments, the stem cell is abone marrow stem cell. In some embodiments, the stem cell is amultipotent hematopoietic stem cell (hemocytoblast). In someembodiments, the disclosure provides for a method of inducingdifferentiation of a cell of the myeloid lineage, the method comprising:administering to the cell an effective amount of one or more of any ofthe compounds disclosed herein. In some embodiments, the cell is in asubject. In some embodiments, the subject is a mammal. In someembodiments, the mammal is a human. In some embodiments, the subject hasany of the myeloid disorders disclosed herein. In some embodiments, theany of the compounds disclosed herein induces differentiation of thecell into a differentiated myeloid cell. In some embodiments, thedifferentiated myeloid cell is a thrombocyte, reticulocyte, erythrocyte,mast cell, basophil, neutrophil, eosinophil, macrophage or a myeloiddendritic cell.

In some embodiments, the methods of the disclosure contemplate using anyof the securinine or norsecurinine analogue compounds described hereinas myeloablative agent in conjunction with bone marrow transplantationand/or stem cell therapies.

In some embodiments, the securinine or norsecurinine analogue compoundsdescribed herein can be administered in a therapeutically effectiveamount to a patient or subject with a disorder characterized by arrestof differentiation of immature myeloid cells. These disorders caninclude, for example, myeloproliferative disorders, such as leukemia,and immunity related diseases.

In other embodiments, treatment of a patient by administration of asecurinine or norsecurinine analogue compound of the present inventionencompasses chemoprevention in a patient susceptible to developingmyeloid leukemia (e.g., at a higher risk, as a result of geneticpredisposition, environmental factors, or the like) and/or in cancersurvivors at risk of cancer recurrence, as well as treatment of amyeloid leukemia patient by inhibiting or causing regression of adisorder or disease.

In some embodiments, effective amounts are amounts of the securinine ornorsecurinine analogue compound effective to induce or promotedifferentiation of the immature or cancerous myeloid cells in thesubject being treated without being cytotoxic to the subject.

In certain embodiments, the present disclosure provides for methods oftreating myeloid disorders in a subject in need thereof by administeringany of the securinine or norsecurinine analogue compounds orcompositions described herein to the subject. In some embodiments, thesubject comprises a cell that is a leukemic or cancer cell. In certainembodiments, the subject in need of treatment has a malignant tumor. Insome embodiments, the subject is a human.

In some embodiments, the subject is newly diagnosed with a myeloiddisorder. In other embodiments, the subject has had a myeloid disorderfor a period of time, and has had one or more prior surgeries or roundsof radiation therapy and/or chemotherapy. In other embodiments, thesubject having a myeloid disorder is treatment naïve to a prior cancertherapeutic. In some embodiments, the subject has a malignant tumor, andthe subject is treated for the malignant tumor. In certain embodiments,the malignancy is a primary malignancy. In other embodiments, thepatient has a secondary malignancy, and the treatment may comprisetreating either or both of the primary or secondary malignancy.

In some embodiments, the present disclosure provides for methods ofincreasing and/or modulating myeloid cell differentiation activityand/or function in a diseased cell, comprising contacting the diseasedcell with any of the securinine or norsecurinine analogue compounds orpharmaceutical compositions described herein. In some embodiments, thepresent disclosure provides for methods of promoting differentiation ofan immature myeloid cell. In some embodiments, the diseased cell is atumor cell. In some embodiments, the diseased cell is a leukemic cell.In some embodiments, the cell is in a subject. In some embodiments, thesubject is a human.

In certain embodiments, the present disclosure provides methods ofdelivering any of the compounds and compositions described herein tocells of the myeloid lineage, including cells in culture (in vitro or exvivo) and cells in a subject. Delivery to cells in culture, such ashealthy cells or cells from a model of disease, has numerous uses. Theseuses include studies of cell differentiation, elucidation of downstreamsignaling pathways such as the MAPK pathway, and assessment of geneexpression under a variety of conditions (e.g., pH) and the like inhealthy or disease contexts. These uses also include studies ofsecurinine and norsecurinine analogue activities and interactions withother molecules, such as proteins, nucleic acids, carbohydrates, ions,lipids, or amino acids. Such interactions can happen within orsuperficially to the cell and alter the molecule's function. Forexample, the securinine and norsecurinine analogues may improvecatalytic activity of a protein by blocking suppressing molecules orimproving access to a catalytic domain or the analogues may inhibit anactive site on a protein, such as a catalytic domain or a binding site.

Delivery to subjects, such as to cells in a subject, has numerous uses.Exemplary therapeutic uses are described below. Moreover, the compoundsand compositions described herein may be used for diagnostic or researchpurposes. For example, a compound of the disclosure may be detectablylabeled and administered to a subject, such as an animal model ofdisease or a patient, and used to image the compound in the subject'scells and/or tissues. Additionally exemplary uses include delivery tocells in a subject, such as to an animal model of disease. By way ofexample, compounds and compositions of the disclosure may be used asreagents and delivered to animals to understand bioactivity, enzymaticactivity, interactions with other molecules, gene expression, andimpacts on animal physiology in healthy or diseased subjects (e.g., ahuman having a myeloid disorder).

In certain embodiments, the present disclosure provides methods oftreating conditions associated with myeloid disorders. Such conditionsinclude, but are not limited to, abnormal red blood cells or platelets,abnormal white blood cells, an increase in myeloblasts, anemia, fever,shortness of breath, easy bruising or bleeding, petechiae, weakness orfatigue, bone or joint pain, swelling in the abdomen, and weight loss orloss of appetite.

These methods involve, in certain embodiments, administering to theindividual a therapeutically effective amount of any of the compounds orcompositions described herein. These methods are particularly aimed attherapeutic treatment of animals, and more particularly, humans. Withrespect to methods for treating myeloid disorders, the disclosurecontemplates all combinations of any of the foregoing aspects andembodiments, as well as combinations with any of the embodiments setforth in the detailed description and examples.

In certain embodiments, the method comprises contacting a cell with anyof the compounds described herein. In certain embodiments, the cell is anormal human lymphocyte, normal human bone marrow, a mouse embryonicfibroblast, a human umbilical vein endothelial cell, a cancer cell or atumor cell. In some embodiments, the cancer or tumor cell is a leukemiccell. In some embodiments, the cancer or tumor cell is a sarcoma cell.In certain embodiments, the method is in a subject in need thereof, suchas a patient having a myeloid disorder.

A myeloid disorder is any disease, disorder or condition associated withaberrant proliferation, differentiation and/or survival of a cell of themyeloid lineage (e.g., a common myeloid progenitor cell). In someembodiments, the myeloid disorder is associated with increasedproliferation of a cell of the myeloid lineage (e.g., myeloid leukemia).In some embodiments, the myeloid disorder is associated with reduceddifferentiation and/or survival of a myeloid cell or a cell of myeloidlineage. In some embodiments, the myeloid disorder is associated withreduced hematopoiesis of cells of the myeloid lineage. In someembodiments, the myeloid disorder is an autoimmune disease. Examples ofmyeloid disorders include, but are not limited to, any one of: acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplasticsyndromes (MDS), myelodysplasia, Myelodysplastic Syndrome (e.g.,refractory anemia (RA), refractory anemia with ring sideroblasts (RARS),refractory anemia with excess blasts (RAEB), refractory anemia withexcess blasts in transformation (RAEBT), and/or chronic myelomonocyticleukemia (CMMoL)), myeloid sarcoma, chloroma, chronic myeloproliferativediseases (CMPD), essential thrombocythemia, polycythemia vera, chronicmyelogenous leukemia, myelofibrosis, myelofibrosis with myeloidmetaplasia (MMM—also known as agnogenic myeloid metaplasia or idiopathicmyelofibrosis), atypical CMD, chronic neutrophilic leukemia, chroniceosinophilic leukemia, systemic mastocytosis, mast cell disease, chronicneutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL),hypereosinophilic syndrome (HES), unclassified MPD (UMPD), chronicmyelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML),Down Syndrome related myeloid disorders, and myeloid processes thatdisplay overlapping features of MDS and CMPD (hybrid CMD). In someembodiments, a subject having a myeloid disorder has a mutation in oneor more of the following genes: JAK2, NPM1, MPL, RAS, RUNX1, ASXL1,BCORL1, CBL, DNMT3A, EZH2, IDH1/IDH2, TET2, UTX, SF3B1, SRSF2,U2AF35/U2AF1, ZRSR2, PTPN11, SH3KBP1, CDKN2A/B, TRIM33, CTNNA1, SOCS1and/or SF3B1. In some embodiments, a myeloid disorder is any of themyeloid disorders described in Murati et al., 2012, BMC Cancer, 12:304.In some embodiments, a myeloid disorder is associated with any one ofmore of the following symptoms: reduced lifespan, aberrant (e.g.,increased) proliferation of a cell of the myeloid lineage, tumorformation, abnormal red blood cells or platelets, abnormal white bloodcells, an increase in myeloblasts, anemia, fever, shortness of breath,easy bruising or bleeding, petechiae, weakness or fatigue, bone or jointpain, swelling in the abdomen, and weight loss or loss of appetite.

In some embodiments, any of the securinine or norsecurinine analoguecompounds or compositions described herein is administered to a myeloiddisorder disease cell (e.g., in vitro or in vivo, such as to a patientin need thereof). In some embodiments, administering a compound orcomposition to a myeloid disorder disease cell comprises systemicallyadministering the compounds or compositions to a subject in needthereof. Moreover, in certain embodiments, administering to a patientrefers to systemic administration.

In certain embodiments, more than one of the compounds described hereincan be administered to a myeloid disorder disease cell, together(simultaneously) or at different times (sequentially). In someembodiments, the myeloid disorder disease cell is in a subject. Inaddition, securinine or norsecurinine analogue compounds of the presentdisclosure can be administered alone or in combination with one or moreadditional agents or treatment modalities.

Any of the compounds or pharmaceutical compositions of the disclosurehave numerous uses, including in vitro and in vivo uses. In vivo usesinclude not only therapeutic uses but also diagnostic and research usesin, for example, any of the foregoing animal models. By way of example,any of the compounds or pharmaceutical compositions of the disclosuremay be used as research reagents and delivered to animals to understandbioactivity, enzymatic activity, gene expression, interactions withother molecules, and impacts on animal physiology in healthy or diseasesanimals.

The terms “treatment”, “treating”, and the like are used herein togenerally mean obtaining a desired pharmacologic and/or physiologiceffect. “Treating” a condition or disease refers to curing as well asameliorating at least one symptom of the condition or disease, andincludes administration of a composition which reduces the frequency of,or delays the onset of, symptoms of a medical condition in a subject inneed relative to a subject which does not receive the composition.“Treatment” as used herein covers any treatment of a disease orcondition of a mammal, particularly a human, and includes: (a)preventing or delaying onset of symptoms of the disease or conditionfrom occurring in a subject which may be predisposed to the disease orcondition but has not yet begun experiencing symptoms; (b) inhibitingthe disease or condition (e.g., arresting its development); or (c)relieving the disease or condition (e.g., causing regression of thedisease or condition, providing improvement in one or more symptoms).For example, “treatment” of a myeloid disorder encompasses a completereversal or cure of the disease, or any range of improvement in symptomsand/or adverse effects attributable to the myeloid disorders. Merely toillustrate, “treatment” of a myeloid disorder may include an improvementin any of the following symptoms or conditions associated with myeloiddisorders (or combination thereof): aberrant cell proliferation, tumorcell formation, abnormal red blood cells or platelets, abnormal whiteblood cells, an increase in myeloblasts, anemia, fever, shortness ofbreath, easy bruising or bleeding, petechiae, blood clotting, deepvenous thrombosis, pulmonary embolism, weakness or fatigue, frequentinfections, unusual paleness, failure to thrive, reduced lifespan, nightsweats, headaches, dizziness, confusion, slurred speech, bone or jointpain, swelling in the abdomen, enlargement of the spleen and/or liver,and weight loss or loss of appetite. Improvements in any of thesesymptoms can be readily assessed according to standard methods andtechniques known in the art. Other symptoms not listed above may also bemonitored in order to determine the effectiveness of treating myeloiddisorders. The population of subjects treated by the method of thedisclosure includes subjects suffering from the undesirable condition ordisease, as well as subjects at risk for development of the condition ordisease. Without wishing to be bound by theory, in certain embodiments,administering any of the compounds or compositions described herein mayhave any one or more of the following effects: decrease in the numbersof abnormal red and white bloods cells and platelets, increase in thedifferentiation of immature myeloid cells, decrease in proliferation ofa cell of the myeloid lineage, decrease in the number of tumor and/orcancer cells (e.g., leukemic cells), decrease in the number ofpetechiae, improvement of anemia, lessening of bone or joint pain,increase in lifespan, improved mental function, and/or reduction inweight loss. It should be noted that any of the compounds orcompositions described above or herein may be used in any of the methodsdescribed herein.

The term “preventing” is art-recognized and includes stopping a disease,disorder or condition from occurring in a subject, which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it. Preventing a condition related to a diseaseincludes stopping the condition from occurring after the disease hasbeen diagnosed but before the condition has been diagnosed.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as a mammal, a fish, abird, a reptile, or an amphibian. Thus, the subject of the hereindisclosed methods can be a human, non-human primate, horse, pig, rabbit,dog, sheep, goat, cow, cat, guinea pig or rodent. The term does notdenote a particular age or sex. Thus, adult and newborn subjects, aswell as fetuses, whether male or female, are intended to be covered. Inone aspect, the subject is a mammal. A patient refers to a subjectafflicted with a disease or disorder.

The terms “prophylactic” or “therapeutic” treatment is art-recognizedand includes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The terms “therapeutic agent”, “drug”, “medicament” and “bioactivesubstance” are art-recognized terms and include molecules and otheragents that are biologically, physiologically, or pharmacologicallyactive substances that act locally or systemically in a patient orsubject to treat a disease or condition. The terms include withoutlimitation pharmaceutically acceptable salts thereof and prodrugs. Suchagents may be acidic, basic, or salts; they may be neutral molecules,polar molecules, or molecular complexes capable of hydrogen bonding;they may be prodrugs in the form of ethers, esters, amides and the likethat are biologically activated when administered into a patient orsubject.

The phrase “therapeutically effective amount” or “pharmaceuticallyeffective amount” is an art-recognized term. In certain embodiments, theterm refers to an amount of a therapeutic agent that produces somedesired effect at a reasonable benefit/risk ratio applicable to anymedical treatment. In certain embodiments, the term refers to thatamount necessary or sufficient to eliminate, reduce or maintain a targetof a particular therapeutic regimen. The effective amount may varydepending on such factors as the disease or condition being treated, theparticular targeted constructs being administered, the size of thesubject or the severity of the disease or condition. One of ordinaryskill in the art may empirically determine the effective amount of aparticular compound without necessitating undue experimentation. Incertain embodiments, a therapeutically effective amount of a therapeuticagent for in vivo use will likely depend on a number of factors,including: the rate of release of an agent from a polymer matrix, whichwill depend in part on the chemical and physical characteristics of thepolymer; the identity of the agent; the mode and method ofadministration; and any other materials incorporated in the polymermatrix in addition to the agent.

By the term “therapeutically effective dose” is meant a dose thatproduces the desired effect for which it is administered. The exact dosewill depend on the purpose of the treatment, and will be ascertainableby one skilled in the art using known techniques (see, e.g., Lloyd(1999) The Art, Science and Technology of Pharmaceutical Compounding).

Combination Therapies

In some embodiments, the securinine or norsecurinine analogue compoundscan be used in combination and adjunctive therapies for treatingproliferative disorders.

In other embodiments, the phrase “combination therapy” embraces theadministration of the any of the compounds described herein and anadditional therapeutic agent as part of a specific treatment regimenintended to provide a beneficial effect from the co-action of thesetherapeutic agents. Administration of these therapeutic agents incombination typically is carried out over a defined time period (usuallyminutes, hours, days or weeks depending upon the combination selected).“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, that is, wherein eachtherapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single capsule having a fixedratio of each therapeutic agent or in multiple, single capsules for eachof the therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent can be effected by anyappropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues. The therapeutic agents can be administered bythe same route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by intravenousinjection while the other therapeutic agents of the combination may beadministered orally. Alternatively, for example, all therapeutic agentsmay be administered orally or all therapeutic agents may be administeredby intravenous injection. The sequence in which the therapeutic agentsare administered is not narrowly critical. “Combination therapy” alsocan embrace the administration of the therapeutic agents as describedabove in further combination with other biologically active ingredients(such as, but not limited to, a second and different therapeutic agent)and non-drug therapies (such as, but not limited to, surgery orradiation treatment). Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

In another example of combination therapy, one or more securinine ornorsecurinine analogue compounds of the disclosure can be used as partof a therapeutic regimen combined with one or more additional treatmentmodalities. By way of example, such other treatment modalities include,but are not limited to, dietary therapy, occupational therapy, physicaltherapy, ventilator supportive therapy, massage, acupuncture,acupressure, mobility aids, assistance animals, speech therapy, languagetherapy, educational therapy, psychological therapy, occupationaltherapy and the like.

In some embodiments the phrase “adjunctive therapy” encompassestreatment of a subject with agents that reduce or avoid side effectsassociated with the combination therapy of the present invention,including, but not limited to, those agents, for example, that reducethe toxic effect of anticancer drugs, e.g., bone resorption inhibitors,cardioprotective agents; prevent or reduce the incidence of nausea andvomiting associated with chemotherapy, radiotherapy or operation; orreduce the incidence of infection associated with the administration ofmyelosuppressive anticancer drugs.

In some embodiments, the mammalian disease treated by the combinationtherapy can include any of the myeloid disorders described herein.Besides being useful for human treatment, the combination therapy isalso useful for veterinary treatment of companion animals, exotic andfarm animals, including rodents, horses, dogs, and cats.

In other embodiments, the therapeutic agents administered in combinationtherapy with the securinine or norsecurinine analogue compounds cancomprise at least one anti-proliferative agent selected from the groupconsisting of a chemotherapeutic agent, an antimetabolite, anantitumorgenic agent, an antimitotic agent, an antiviral agent, anantineoplastic agent, an immunotherapeutic agent, and a radiotherapeuticagent.

In some embodiments, the phrase “anti-proliferative agent” can includeagents that exert antineoplastic, chemotherapeutic, antiviral,antimitotic, antitumorgenic, and/or immunotherapeutic effects, e.g.,prevent the development, maturation, or spread of neoplastic cells,directly on the tumor cell, e.g., by cytostatic or cytocidal effects,and not indirectly through mechanisms such as biological responsemodification. There are large numbers of anti-proliferative agent agentsavailable in commercial use, in clinical evaluation and in pre-clinicaldevelopment, which could be included in the present invention bycombination drug chemotherapy. For convenience of discussion,anti-proliferative agents are classified into the following classes,subtypes and species: ACE inhibitors, alkylating agents, angiogenesisinhibitors, angiostatin, anthracyclines/DNA intercalators, anti-cancerantibiotics or antibiotic-type agents, antimetabolites, antimetastaticcompounds, asparaginases, bisphosphonates, cGMP phosphodiesteraseinhibitors, calcium carbonate, cyclooxygenase-2 inhibitors, DHAderivatives, DNA topoisomerase, endostatin, epipodophylotoxins,genistein, hormonal anticancer agents, hydrophilic bile acids (URSO),immunomodulators or immunological agents, integrin antagonists,interferon antagonists or agents, MMP inhibitors, miscellaneousantineoplastic agents, monoclonal antibodies, nitrosoureas, NSAIDs,ornithine decarboxylase inhibitors, pBATTs, radio/chemosensitizers/protectors, retinoids, selective inhibitors of proliferationand migration of endothelial cells, selenium, stromelysin inhibitors,taxanes, vaccines, and vinca alkaloids.

The major categories that some anti-proliferative agents fall intoinclude antimetabolite agents, alkylating agents, antibiotic-typeagents, hormonal anticancer agents, immunological agents,interferon-type agents, and a category of miscellaneous antineoplasticagents. Some anti-proliferative agents operate through multiple orunknown mechanisms and can thus be classified into more than onecategory.

In some embodiments a first family of anti-proliferative agents, whichmay be used in combination therapy with any of the compounds describedherein, consists of antimetabolite-type anti-proliferative agents.Antimetabolites are typically reversible or irreversible enzymeinhibitors, or compounds that otherwise interfere with the replication,translation or transcription of nucleic acids. Examples ofantimetabolite antineoplastic agents that may be used in the presentinvention include, but are not limited to acanthifolic acid,aminothiadiazole, anastrozole, bicalutamide, brequinar sodium,capecitabine, carmofur, Ciba-Geigy CGP-30694, cladribine, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates,cytarabine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezaguanine,dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine,Wellcome EHNA, Merck & Co. EX-015, fazarabine, finasteride, floxuridine,fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil, Daiichi SeiyakuFO-152, fluorouracil (5-FU), 5-FU-fibrinogen, isopropyl pyrrolizine,Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, WellcomeMZPES, nafarelin, norspermidine, nolvadex, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, stearate;Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate,tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, TaihoUFT, toremifene, and uricytin, all of which are disclosed in U.S. Pat.No. 6,916,800, which is herein incorporated by reference in itsentirety.

In some embodiments, a second family of anti-proliferative agents, whichmay be used in combination therapy with any of the compounds describedherein, consists of alkylating-type anti-proliferative agents. Thealkylating agents are believed to act by alkylating and cross-linkingguanine and possibly other bases in DNA, arresting cell division.Typical alkylating agents include nitrogen mustards, ethyleneiminecompounds, alkyl sulfates, cisplatin, and various nitrosoureas. Adisadvantage with these compounds is that they not only attack malignantcells, but also other cells which are naturally dividing, such as thoseof bone marrow, skin, gastro-intestinal mucosa, and fetal tissue.Examples of alkylating-type anti-proliferative agents that may be usedin the present invention include, but are not limited to, Shionogi254-S, aldo-phosphamide analogues, altretamine, anaxirone, BoehringerMannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine (BiCNU), Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, dacarbazine, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, etoposide phosphate, fotemustine, UnimedG-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin,lomustine, mafosfamide, mitolactol, mycophenolate, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772,thiotepa, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077,tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.

In some embodiments, a third family of anti-proliferative agents thatmay be used in combination therapy with the securinine or norsecurinineanalogue compounds of the present invention consists of antibiotic-typeanti-proliferative agents. Examples of antibiotic-typeanti-proliferative agents that may be used in the present inventioninclude, but are not limited to Taiho 4181-A, aclarubicin, actinomycinD, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, AjinomotoAN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline,azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-MyersBMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605,Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate,bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin,daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A,Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, ShionogiDOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin,erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, ErbamontFCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin,kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa HakkoKT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American CyanamidLL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone,SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon KayakuNKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

In some embodiments, a fourth family of anti-proliferative agents thatmay be used in combination therapy with any of the compounds describedherein consists of synthetic nucleosides. Several synthetic nucleosideshave been identified that exhibit anticancer activity. A well knownnucleoside derivative with strong anticancer activity is 5-fluorouracil(5-FU). 5-Fluorouracil has been used clinically in the treatment ofmalignant tumors, including, for example, carcinomas, sarcomas, skincancer, cancer of the digestive organs, and breast cancer.5-Fluorouracil, however, causes serious adverse reactions such asnausea, alopecia, diarrhea, stomatitis, leukocytic thrombocytopenia,anorexia, pigmentation, and edema. Derivatives of 5-fluorouracil withanti-cancer activity have been described in U.S. Pat. No. 4,336,381,which is herein incorporated by reference in its entirety.

In some embodiments, a fifth family of anti-proliferative agents thatmay be used in combination therapy with any of the compounds describedherein consists of hormonal agents. Examples of hormonal-typeanti-proliferative agents that may be used in the present inventioninclude, but are not limited to Abarelix; Abbott A-84861; Abirateroneacetate; Aminoglutethimide; anastrozole; Asta Medica AN-207; Antide;Chugai AG-041R; Avorelin; aseranox; Sensus B2036-PEG; Bicalutamide;buserelin; BTG CB-7598; BTG CB-7630; Casodex; cetrolix; clastroban;clodronate disodium; Cosudex; Rotta Research CR-1505; cytadren; crinone;deslorelin; droloxifene; dutasteride; Elimina; Laval University EM-800;Laval University EM-652; epitiostanol; epristeride; Mediolanum EP-23904;EntreMed 2-ME; exemestane; fadrozole; finasteride; flutamide;formestane; Pharmacia & Upjohn FCE-24304; ganirelix; goserelin; Shiregonadorelin agonist; Glaxo Wellcome GW-5638; Hoechst Marion RousselHoe-766; NCI hCG; idoxifene; isocordoin; Zeneca ICI-182780; ZenecaICI-118630; Tulane University J015X; Schering Ag J96; ketanserin;lanreotide; Milkhaus LDI-200; letrozol; leuprolide; leuprorelin;liarozole; lisuride hydrogen maleate; loxiglumide; mepitiostane;Leuprorelin; Ligand Pharmaceuticals LG-1127; LG-1447; LG-2293; LG-2527;LG-2716; Bone Care International LR-103; Lilly LY-326315; LillyLY-353381-HCl; Lilly LY-326391; Lilly LY-353381; Lilly LY-357489;miproxifene phosphate; Orion Pharma MPV-2213ad; Tulane UniversityMZ-4-71; nafarelin; nilutamide; Snow Brand NKS01; octreotide; Azko NobelORG-31710; Azko Nobel ORG-31806; orimeten; orimetene; orimetine;ormeloxifene; osaterone; Smithkline Beecham SKB-105657; Tokyo UniversityOSW-1; Peptech PTL-03001; Pharmacia & Upjohn PNU-156765; quinagolide;ramorelix; Raloxifene; statin; sandostatin LAR; Shionogi S-10364;Novartis SMT-487; somavert; somatostatin; tamoxifen; tamoxifenmethiodide; teverelix; toremifene; triptorelin; TT-232; vapreotide;vorozole; Yamanouchi YM-116; Yamanouchi YM-511; Yamanouchi YM-55208;Yamanouchi YM-53789; Schering AG ZK-1911703; Schering AG ZK-230211; andZeneca ZD-182780.

In some embodiments, a sixth family of anti-proliferative agents thatmay be used in combination therapy with any of the compounds describedherein consists of a miscellaneous family of antineoplastic agentsincluding, but not limited to alpha-carotene,alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52,alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin,anti-neoplaston A10, antineoplaston A2, antineoplaston A3,antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolinglycinate, asparaginase, Avarol, baccharin, batracylin, benfluoron,benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-MyersBMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, WellcomeBW-773, calcium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane calciumcarbonate tablets, caracemide, carmethizole hydrochloride, AjinomotoCDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Cell Pathways CP-461, Yakult Honsha CPT-11,crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609,DABIS maleate, dacarbazine, datelliptinium, DFMO, didemnin-B,dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel,Encore Pharmaceuticals E7869, elliprabin, elliptinium acetate, TsumuraEPMTC, ergotamine, etoposide, etretinate, Eulexin®, Cell PathwaysExisulind® (sulindac sulphone or CP-246), fenretinide, Merck ResearchLabs Finasteride, Florical, Fujisawa FR-57704, gallium nitrate,gemcitabine, genkwadaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, irinotecan,isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, ketoconazole,Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, AmericanCyanamid L-623, leucovorin, levamisole, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, Monocal, mopidamol, motretinide,Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids, Nilandron;Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom,Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative, Normosang,NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580,octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, retinoids, Encore Pharmaceuticals R-flurbiprofen,Sandostatin; Sapporo Breweries RBS, restrictin-P, retelliptine, retinoicacid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Scherring-PloughSC-57050, Scherring-Plough SC-57068, seienium(selenite andselenomethionine), SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, Sugen SU-101, SugenSU-5416, Sugen SU-6668, sulindac, sulindac sulfone; superoxidedismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303,teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides,Yamanouchi YM-534, Zileuton, ursodeoxycholic acid, and Zanosar.

In some embodiments, any of the compounds described herein can allow thecombination therapeutic agents and/or compounds described herein to beadministered at a low dose, that is, at a dose lower than has beenconventionally used in clinical situations.

A benefit of lowering the dose of the combination therapeutic agents andany of the securinine or norsecurinine analogue compounds describedherein administered to a mammal includes a decrease in the incidence ofadverse effects associated with higher dosages. For example, by thelowering the dosage of a chemotherapeutic agent such as methotrexate, areduction in the frequency and the severity of nausea and vomiting willresult when compared to that observed at higher dosages. Similarbenefits are contemplated for the compounds, compositions, agents andtherapies in combination with the inhibitors of the present invention.

In some embodiments, by lowering the incidence of adverse effects, animprovement in the quality of life of a patient undergoing treatment forcancer is contemplated. Further benefits of lowering the incidence ofadverse effects include an improvement in patient compliance, areduction in the number of hospitalizations needed for the treatment ofadverse effects, and a reduction in the administration of analgesicagents needed to treat pain associated with the adverse effects.

Alternatively, the methods and combination of the present invention canalso maximize the therapeutic effect at higher doses.

In some embodiments, when administered as a combination, the therapeuticagents can be formulated as separate compositions which are given at thesame time or different times, or the therapeutic agents can be given asa single composition.

Methods of Administration

Various delivery systems are known and can be used to administer thepharmaceutical compositions of the disclosure to a subject. Any suchmethods may be used to administer to a subject any of the pharmaceuticalcompositions described herein. The disclosure contemplates that any ofthe methods of administration described herein may be combined with anyof the methods disclosure herein. In some embodiments the pharmaceuticalcompositions of the present invention can be administered by any meansthat achieve their intended purpose. For example, administration can beby parenteral, subcutaneous, intravenous, intraarticular, intrathecal,intramuscular, intraperitoneal, or intradermal injections, or bytransdermal, buccal, oromucosal, ocular routes or via inhalation. Thepharmaceutical compositions may be administered by any convenient route,for example, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.) and may be administered together with otherbiologically active agents. Administration can be systemic or local.

Alternatively or concurrently, administration can be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the patient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

In certain embodiments, it may be desirable to administer thepharmaceutical compositions of the disclosure locally to the area inneed of treatment; this may be achieved, for example, and not by way oflimitation, by local infusion during surgery, by means of a catheter, orby means of an implant, the implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,fibers, or commercial skin substitutes.

Note that the disclosure contemplates methods in which pharmaceuticalcompositions are administered, at the same or different times, via onethan one route of administration. For example, the disclosurecontemplates a regimen in which the pharmaceutical compositions areadministered systemically, such as by intravenous infusion, incombination with local administration via the hepatic portal vein.

In other embodiments, any of the pharmaceutical compositions describedherein can be delivered in a vesicle, in particular, a liposome (seeLanger, 1990, Science 249:1527-1533). In yet another embodiment, thepharmaceutical compositions of the disclosure can be delivered in acontrolled release system. In another embodiment, a pump may be used(see Langer, 1990, supra). In another embodiment, polymeric materialscan be used (see Howard et al., 1989, J. Neurosurg. 71:105). In certainspecific embodiments, the pharmaceutical compositions of the disclosurecan be delivered intravenously.

The phrases “parenteral administration” and “administered parenterally”are art-recognized terms, and include modes of administration other thanenteral and topical administration, such as injections, and include,without limitation, intravenous, intramuscular, intrapleural,intravascular, intrapericardial, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

Pharmaceutical Compositions

In some embodiments, any of the compounds described herein can beprovided in the form of pharmaceutical compositions. The pharmaceuticalcompositions can be administered to any mammal that can experience thebeneficial effects of the securinine or norsecurinine analogue compoundsof the present invention. Foremost among such animals are humans,although the present invention is not intended to be so limited.

In some embodiments, in addition to the pharmacologically activecompounds, the pharmaceutical preparations of the securinine ornorsecurinine analogue compounds can contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active agents into preparations that can beused pharmaceutically. The pharmaceutical preparations of the presentinvention are manufactured in a manner that is, itself, known, forexample, by means of conventional mixing, granulating, dragee-making,dissolving, or lyophilizing processes. Thus, pharmaceutical preparationsfor oral use can be obtained by combining the active agents with solidexcipients, optionally grinding the resulting mixture and processing themixture of granules, after adding suitable auxiliaries, if desired ornecessary, to obtain tablets or dragee cores.

In other embodiments, suitable excipients are, in particular, fillerssuch as saccharides, for example, lactose or sucrose, mannitol orsorbitol, cellulose preparations and/or calcium phosphates, for example,tricalcium phosphate or calcium hydrogen phosphate, as well as binders,such as starch paste, using, for example, maize starch, wheat starch,rice starch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings that, if desired, are resistant to gastric juices. Forthis purpose, concentrated saccharide solutions can be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol, and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, areused. Slow-release and prolonged-release formulations may be used withparticular excipients such as methacrylic acid-ethylacrylate copolymers,methacrylic acid-ethyl acrylate copolymers, methacrylic acid-methylmethacrylate copolymers and methacrylic acid-methyl methylacrylatecopolymers. Dye stuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

In some embodiments, other pharmaceutical preparations that can be usedorally include push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer such as glycerol orsorbitol. The push-fit capsules can contain the active compounds in theform of granules that may be mixed with fillers such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active compounds maybe dissolved or suspended in suitable liquids such as fatty oils orliquid paraffin. In addition, stabilizers may be added.

In some embodiments, formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form, forexample, water-soluble salts and alkaline solutions. In someembodiments, salts are maleate, fumarate, succinate, S,S tartrate, orR,R tartrate. In addition, suspensions of the active compounds asappropriate oily injection suspensions can be administered. Suitablelipophilic solvents or vehicles include fatty oils, for example, sesameoil, or synthetic fatty acid esters, for example, ethyl oleate ortriglycerides or polyethylene glycol-400 (the compounds are soluble inPEG-400). Aqueous injection suspensions can contain substances thatincrease the viscosity of the suspension, for example sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. Optionally, thesuspension may also contain stabilizers.

The term “pharmaceutical composition” refers to a formulation containingthe disclosed compounds in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler, or a vial. The quantity of active ingredient (e.g.,a formulation of the disclosed compound or salts thereof) in a unit doseof composition is an effective amount and is varied according to theparticular treatment involved. One skilled in the art will appreciatethat it is sometimes necessary to make routine variations to the dosagedepending on the age and condition of the patient. The dosage will alsodepend on the route of administration. A variety of routes arecontemplated, including oral, pulmonary, rectal, parenteral,transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,intranasal, inhalational, and the like. Dosage forms for the topical ortransdermal administration of a compound described herein includespowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches, nebulized compounds, and inhalants. In one embodiment, theactive compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that are required.

The term “flash dose” refers to compound formulations that are rapidlydispersing dosage forms.

The term “immediate release” is defined as a release of compound from adosage form in a relatively brief period of time, generally up to about60 minutes. The term “modified release” is defined to include delayedrelease, extended release, and pulsed release. The term “pulsed release”is defined as a series of releases of drug from a dosage form. The term“sustained release” or “extended release” is defined as continuousrelease of a compound from a dosage form over a prolonged period.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting any subject composition from one organ, or portion of thebody, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof a subject composition and not injurious to the patient. In certainembodiments, a pharmaceutically acceptable carrier is non-pyrogenic.Some examples of materials which may serve as pharmaceuticallyacceptable carriers include: (1) sugars, such as lactose, glucose andsucrose; (2) starches, such as corn starch and potato starch; (3)cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5)malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter andsuppository waxes; (9) oils, such as peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10)glycols, such as propylene glycol; (11) polyols, such as glycerin,sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyloleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19)ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations.

Animal/Cell Models

Myeloid disorders been modeled in animals such as mice. For example,mice expressing NuMA-RARa carry a genetic myeloproliferationcharacterized by increased granulopoiesis, impaired neutrophildifferentiation, abnormal cytokine response, and responsiveness to ATRA.The disease observed in these mice is progressive and contains manycharacteristics of acute promyelocyctic leukemia (APL) (Sukhai et al.,2004, Oncogene, 23, 665-678).

To generate a murine xenograft model of acute myeloid leukemia, HL-60 orMV4-11 leukemic cells may be implanted into athymic nude mice (CharlesRiver Laboratories) by subcutaneous injection.

Further mice models of myeloid disorders include any of the mouse modelsdescribed in Beachy et al., 2010, Hematol. Oncol. Clin. North Amer.,24(2): 361-375 (which is incorporated herein in its entirety), includingmice carrying Pten^(+/−); Ship^(−/−) mutations, mice overexpressingEvil, mice having Npm^(+/−) mutations, mice having Dido^(−/−) mutations,NUP98-HOXD13 mice, mice overexpressing Sall4B, mice overexpressing Bcl-2and expressing NRASD12 mutations, mice engrafted with immortalized celllines from MDS patients, mice having the Poly^(A/A) mutation, micehaving the Arid4a^(−/−) mutation, mice having the RUNX1 D171N mutation,and/or mice having the AML-S291fsX300 mutation.

In addition, cell models for assessing myeloid disorders are available.For example, HL-60 cells are a cell line model for acute myeloidleukemia (AML)(ATCC). Other leukemic cell lines include KASUMI-1, THP-1,K-562, MOLT-4, MOLT-3, OCI-AML3, and MV4-11 (ATCC).

In some embodiments, the compounds and pharmaceutical compositionsdisclosed herein will be tested on normal human lymphocytes, normalhuman bone marrow, mouse embryonic fibroblasts, human umbilical veinendothelial cells, and cancer cell lines. The effects of the compoundsand pharmaceutical compositions on cell proliferation, cell cyclekinetics, differentiation, and cell death/toxicity can be assessed. Forexample, securinine potently inhibits the proliferation of HL-60 cells;leads to the accumulation of cells in G0/G1; can differentiate a varietyof leukemic cell lines; and exhibits low toxicity across 60 cancer celllines, normal human lymphocytes, normal human bone marrow, mouseembryonic fibroblasts, and human umbilical vein endothelial cells. Anyof the compounds disclosed herein can be similarly tested for similareffects on cells, such as HL-60 cells. Soft agar colony assays can beutilized to study inhibition of colony formation and assess thecompounds and pharmaceutical compositions abilities to induce terminaldifferentiation (U.S. patent application Ser. No. 14/029,066).

In an aspect of the present disclosure, the compounds of the disclosurecan be identified using a novel high-throughput screen that is biased toidentify agents that have both a high potency and low toxicity in amyeloid disorder disease model, such as an animal or cell model. In someembodiments, the high-throughput screen measures the differentiation ofHL-60 leukemic cells using a quantitative nitroblue tetrazolium (NBT)reduction assay. Screening HL-60 cells, human promyelocytic cells, isadvantageous as they have been used extensively as a cell line to studymyeloid differentiation. Though promyelocytic cells, HL-60 cells werederived from a patient with acute myeloblastic leukemia with maturation,FAB-M2. This cell line has been shown to be an appropriate model tostudy myeloid differentiation as it undergoes terminal differentiationto either granulocytic or monocytic pathways with numerous knowncompounds. The differentiated cells demonstrate all of the expectedfunctional properties such as chemotaxis, bacterial killing, ingestion,and respiratory burst activity.

Nitroblue Tetrazolium (NBT) reduction has been widely demonstrated toprovide a very accurate correlation to the extent of myeloiddifferentiation to both granulocytic and monocytic pathways. Thistechnique has also been widely exploited in HL-60 cells to analyzemyelomonocytic differentiation. In fact, it has been routinelydemonstrated for over 20 years that the NBT test provides an extremelyclose correlation with the morphology of the differentiated cells.

The NBT screen works due to changes in the oxidoreductases duringdifferentiation that lead to increases in rates of NBT reduction. NBT isreduced due to the production of superoxide that is catalyzed by anNADPH oxidase. This enzyme is inactive in resting cells, therefore, itis necessary to treat the cells with PMA to generate an oxidative burst.NBT is reduced by superoxide from a soluble yellow compound to insolubleblue formazan granules whose formation can be monitoredspectrophotometrically at 560 nm as the unreduced dye has minimalabsorbance at this wavelength. A quantitative NBT reduction assay isideal for this type of screen as it is simple, sensitive, quantitative,requires minimal cells, has been proven to have low well to wellvariability, and the amount of reduced NBT is proportional to the numberof cells reducing the dye as well as the amount reduced by each cell.

The above models are exemplary of suitable animal and cell model systemsfor assessing the activity and effectiveness of the compounds andpharmaceutical compositions and/or formulations. These models havecorrelations with symptoms of myeloid disorders, and thus provideappropriate models. Activity of the subject compounds and pharmaceuticalcompositions and/or formulations are assessed in any one or more ofthese models, and the results compared to that observed in wildtypecontrol animals and/or cells, and animals and/or cells not treated withthe compounds and pharmaceutical compositions. In some embodiments, thesubject compounds and pharmaceutical compositions are evaluated usingcells prepared from any of the foregoing mutant mice or other animals,as well as wild type cells, such as fibroblasts and lymphocytes. Theseassays have been described in U.S. patent application Ser. No.14/029,066, hereby incorporated by reference.

Moreover, in vitro systems may be used to evaluate the ability of any ofthe compounds or pharmaceutical compositions to mediate gene expression.For example, in some embodiments, gene expression of cells treated withany of the compounds or pharmaceutical compositions of interest isassessed at 16 and 72 hours after treatment using gene microarrays.Results are compared to that observed in control cells or cells nottreated with the compounds and pharmaceutical compositions (U.S. patentapplication Ser. No. 14/029,066).

In vitro systems can be utilized to demonstrate the capability of thesecompounds and pharmaceutical compositions to induce differentiation asmeasured by morphologic changes, up-regulation of the cell surfacemarkers, and NBT reduction. For example, securinine induces clearmorphologic changes suggestive of monocytic differentiation, asevidenced by indented and condensed nuclei that lack prominent nucleoliand more abundant and vacuolated cytoplasm. Flow cytometric analysissupports that securinine leads to monocytic differentiation. While thecell surface marker CD11b is induced during both granulocytic andmonocytic differentiation, the marker CD14 is specific to monocyticdifferentiation. Securinine and the known monocyticdifferentiation-inducing agent vitamin D3 induce CD14 and CD11b, whileATRA, a granulocytic differentiation-inducing agent, primarily inducesCD11b. From the NBT reduction assay, securinine has similar activity toATRA in HL-60 cells as ˜95% of cells are differentiated by thesecompounds (U.S. patent application Ser. No. 14/029,066). Any of thecompounds disclosed herein can be tested in similar assays.

Additionally, in vitro systems can be used to compare the activity ofthe compounds or pharmaceutical compositions disclosed with the activityof known differentiation-inducing agents such as ATRA and vitamin D3.For example, the expression of the transcription factor CEBPβ is knownto be critical for monocytic differentiation, and securinine was foundto induce a time-dependent upregulation of CEBPβ. Similarly, thetranscription factor c-myc, important in regulating cell proliferationand known to be downregulated during terminal differentiation, waspotently downregulated by securinine Securinine was found to cause cellsto accumulate in the G0/G1 phase of the cell cycle. The protein p21 isknown to block the G1 to S phase transition by repressing the cyclinD/CDK4/6 complex, and as is common with other differentiation-inducingcompounds such as ATRA, the p21 protein was upregulated by securinineFinally, several other characterized differentiation-inducers activateMAPK signaling pathways, and securinine induces rapid phosphorylation ofp44/p42 and p38 (U.S. patent application Ser. No. 14/029,066). Any ofthe compounds disclosed herein can be tested in similar assays.

In some embodiments, in vitro systems can be used to study theinteractions of securinine and norsecurinine analogues with othermolecules, such as proteins, nucleic acids, carbohydrates, ions, lipids,or amino acids. Such interactions can happen within or superficially tothe cell and alter the molecule's function. For example, the securinineand norsecurinine analogues may improve catalytic activity of a proteinby blocking suppressing molecules or improving access to a catalyticdomain or the analogues may inhibit an active site on a protein, such asa catalytic domain or a binding site.

The effects of any of the pharmaceutical compositions and compoundsdisclosed herein may be tested in any of the cells or animal modelsdisclosed herein.

The pharmaceutical compositions and compounds of the disclosure havenumerous uses, including in vitro and in vivo uses. In vivo uses includenot only therapeutic uses but also diagnostic and research uses in, forexample, any of the foregoing animal models. By way of example,pharmaceutical compositions and compounds of the disclosure may be usedas research reagents and delivered to animals to understand bioactivity,enzymatic activity, gene expression, interactions with other molecules,and impacts on animal physiology in healthy or diseased animals orcells.

Kits

In certain embodiments, the disclosure also provides a pharmaceuticalpackage or kit comprising one or more containers filled with at leastone compound or composition of the disclosure. Optionally associatedwith such container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects (a)approval by the agency of manufacture, use or sale for humanadministration, (b) directions for use, or both. In certain embodiments,the kit comprises at least two containers, at least one of whichcontains at least one compound or composition of the disclosures. Incertain embodiments, the kit contains at least two containers, and eachof at least two containers contains a compound or composition of thedisclosure.

In certain embodiments, the kit includes additional materials tofacilitate delivery of the subject compounds or compositions. Forexample, the kit may include one or more of a catheter, tubing, infusionbag, syringe, and the like. In certain embodiments, the compounds orcompositions are packaged in a lyophilized form, and the kit includes atleast two containers: a container comprising the lyophilized compoundsor compositions and a container comprising a suitable amount of water,buffer, or other liquid suitable for reconstituting the lyophilizedmaterial.

The foregoing applies to any of the compounds, compositions, and methodsdescribed herein. The disclosure specifically contemplates anycombination of the features of such compounds, compositions, and methods(alone or in combination) with the features described for the variouskits described in this section.

Preparation of the Compounds of the Invention

In some embodiments, one or more of the compounds, or components to makethe compounds, of Formula (I), Formula (II), Formula (III), Formula (IV)or Formula (IV′) are commercially available, for example from commercialsources such as Sigma-Aldrich® of St. Louis, Mo., USA; TCI America,Portland, Oreg., USA; and Acros Organics, Geel, Belgium; among others.They may be natural (e.g. extracted from biomass or naturallysynthesized by microbes or enzymatically) or synthetic.

In some embodiments, one or more of the compounds of Formula (I),Formula (I′), Formula (II), Formula (III), Formula (IV) or Formula (IV′)are prepared from commercially available reagents by routine methods insynthetic organic chemistry.

Compounds of Formula (I), Formula (I′), and Formula (II)

In one embodiment, one or more compounds of Formula (I), Formula (I′),and Formula (II) were prepared by the multi-step synthetic sequencedescribed below. One of skill in the art would be able to readily adaptthe described conditions for the synthesis of compounds of Formula (I),Formula (I′), and Formula (II).

The γ-iodo derivatives of securinine and norsecurinine (1 and 14) wereprepared from securinine using N-iodosuccinimide in MeOH (J.-Y. Li, etal., Tetrahedron, 2012, 68, 21, 3972-3979, which is hereby incorporatedby reference). During the product isolation from the reaction mixture,side products 1 and 2 were also isolated. Using the intermediates 1 and14, further analogues of securinine and norsecurinine were prepared.

In one embodiment, the C-14 alkyl/aryl analogues of securinine wereprepared using 14 and the corresponding boronic acids/esters.Bis(triphenylphosphine)palladium(II)dichloride (7 mg, 0.01 mmol) wasadded to a stirred solution of 14 (34.3 mg, 0.1 mmol) in anhydroustoluene or tetrahydrofuran (0.75 mL) followed by the correspondingboronic acid (0.2 mmol) and then potassium carbonate/water (20 mg, 0.15mmol/75 uL). The reaction mixture was degassed under nitrogen atmospherefor 15 minutes and then gradually heated to 80° C. to 100° C. Thereaction progress was monitored by thin layer chromatography (TLC) andthe reaction mixture was stirred at that temperature for 1 to 2 hoursuntil the starting material was completely consumed. The reactionmixture was poured in water (2 mL) and extracted with ethyl acetate (2×3mL) and the combined organic layers were washed with brine (5 mL), driedover sodium sulfate and concentrated on a rotary evaporator. The crudeproduct was dried under high vacuum and purified by silica gelchromatography using an appropriate solvent system to afford the desiredC-14 alkyl/aryl analogue of securinine in 40-70% yield (Scheme 1):

Compounds of Formula (III)

In one embodiment, one or more compounds of Formula (III) were preparedby the synthetic sequence described below. One of skill in the art wouldbe able to readily adapt the described conditions for the synthesis ofcompounds of Formula (III).

To a solution of 14 (26 mg, 0.075 mmol) in anhydrous1,4-dioxane/tetrahydrofuran (0.75 mL) was addedbis(triphenylphosphine)palladium(II)dichloride (2.6 mg, 0.00375 mmol),CuI (1.5 mg, 0.0075 mmol) and triethylamine (52 uL, 0.375 mmol). Thereaction mixture was degassed under nitrogen atmosphere for 10 minutesand then gradually heated to 80° C. At this point, the reaction mixtureturned into homogeneous, clear, dark brown solution. The reaction wasbrought to room temperature and the corresponding alkyne (0.1125 mmol)was added. The reaction progress was monitored by thin layerchromatography (TLC) and the reaction mixture was stirred at roomtemperature for 1 to 2 hours until the starting material was completelyconsumed. The reaction mixture was poured into water (2 mL) andextracted with ethyl acetate (2×3 mL) and the combined organic layerswere washed with brine (5 mL), dried over sodium sulfate andconcentrated on a rotary evaporator. The crude product was dried underhigh vacuum and purified by silica gel chromatography using anappropriate solvent system to afford the corresponding C-14 alkynylanalogue of securinine Alkynyl analogues of securinine and norsecurininehave been synthesized employing the above procedure in 50-90% yield(Scheme 2):

Compounds of Formula (IV) and Formula (IV′)

In one embodiment, one or more compounds of Formula (IV) and Formula(IV′) were prepared by the synthetic sequence described below. One ofskill in the art would be able to readily adapt the described conditionsfor the synthesis of compounds of Formula (IV) and Formula (IV′).

In one variation, C-15 analogues of securinine were prepared by1,6-conjugate addition of thials/amines following the general procedureoutlined below.

54.3 mg of securinine (0.25 mmol) and 0.3-0.4 mmol of the correspondingamine/thial were weighed in an oven dried reaction flask equipped with asepta or a 4 mL vial with a Teflon cap. 1 mL of acetonitrile followed bytriethylamine (139 uL, 1 mmol) was added and the reaction mixture wasstirred under nitrogen atmosphere at room temperature. The reactionmixture was monitored by thin layer chromatography (TLC). The reactionmixture was allowed to stir from 8 hours to 2 days at room temperatureuntil the starting material was completely consumed or maximum productformation was observed. All the volatiles in the reaction mixture wereevaporated under reduced pressure and the crude product was purified byflash column chromatography on silica gel, using an appropriatehexanes/acetone solvent system. C-15 analogues of securinine have beensynthesized employing the above procedure in 55-95% yield (Scheme 3):

Salts of Securinine and Norsecurinine Analogues

In one embodiment, one or more salts of securinine or norsecurinineanalogues were prepared by the method described below. One of skill inthe art would be able to readily adapt the described conditions togenerate salts of securinine and norsecurinine analogues disclosed inthe invention.

Securinine or norsecurinine analogues were dissolved in 1,4-dioxane andadded to a 2N HCl/1,4-dioxane solution mixture at 0° C. The reactionmixture was stirred as the product slowly precipitates. Hexanes or etherwere then added and the solids filtered and washed to obtain thecorresponding HCl salts.

Similarly, a securinine or norsecurinine analogue was dissolved inmethanol and to this mixture, tartaric acid was added. The reactionmixture was gradually heated to 80° C. as the product slowlyprecipitates. Ether was then added and the solids filtered and washed toobtain the corresponding tartarate salts.

EXEMPLIFICATION

The disclosure now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present disclosure, and are not intended to limit the disclosure.For example, the particular constructs and experimental design disclosedherein represent exemplary tools and methods for validating properfunction. As such, it will be readily apparent that any of the disclosedspecific constructs and experimental plan can be substituted within thescope of the present disclosure.

Example 1 Identification of Novel Differentiation-Inducing Compounds

To discover novel AML differentiation-inducing compounds a rapidhigh-throughput screen (HTS) was developed and optimized. The screen wasdesigned to be biased to identify compounds that, unlike the majority ofknown differentiation-inducing agents, have both high potency and lowtoxicity. The screen measured the differentiation of HL-60 leukemiccells using a quantitative Nitroblue Tetrazolium (NBT) reduction assay,a test that is used extensively as a measure of functionalmyelomonocytic differentiation. The basis for the screen is unreducedNBT exists as a yellow soluble dye. Differentiated leukemic cells arecapable of producing a respiratory burst that can reduce NBT into a blueinsoluble compound that can be measured spectrophotometrically. Thisforward chemical genetics approach allowed the discovery of novelcompounds that can act on targets not previously known to be “drugable.”As only live cells can reduce NBT, the screen is biased in identifyingrelatively nontoxic compounds.

To perform the screen, duplicate plates of HL-60 cells were cultured ata density of 5×104 cells/mL with 10 μM of each compound in 96 wellplates for 5 days. To determine the relative capability for a compoundto induce differentiation compared to known potent inducers, each platedestined for the NBT reduction assay included wells with 0.1% DMSO(vehicle control) and 1 μM ATRA. This approach eliminates any slight dayto day variation in NBT reduction values and allows the discovery ofcompounds with similar or greater efficacy to ATRA. Differentiation wasdetermined in the 96 well plates by incubating the cells with 1 mg/mL ofNBT and 200 ng/mL of PMA as the stimulant for the respiratory burst for35 minutes at 37° C. The reaction was then stopped with HCl and theformazan solubilized with DMSO. Finally, the reaction mixture was readspectrophotometrically at 560 nm in a plate reader.

The securinine and norsecurinine analogues were tested and evaluated ontheir abilities to affect differentiation and growth of HL-60 cells(Table 1).

TABLE 1 Analogue HL-60, Dif₅₀/IC₅₀ Securinine 10 < Dif₅₀ < 15  74 15 <Dif₅₀ < 20  75 15 < Dif₅₀ < 20 INVS-MG-3B-I & 3B-II 15 < Dif₅₀ < 20  6630 < Dif₅₀ < not tested INVS-MG-5B 30 < Dif₅₀ < not tested  67 20 <Dif₅₀ < 30  68 30 < Dif₅₀ < not tested INVS-MG-12A 0.5 < Dif₅₀ < 0.75 69 20 < Dif ≦ 30  70 10 < Dif₅₀ < 15  71 20 < Dif₅₀ < 30  72 20 < Dif₅₀< 30  73 10 < Dif < 15  79 10 < Dif₅₀ < 15  80 20 < Dif₅₀ < 30  81 10 <Dif₅₀ < 15  82 15 < Dif₅₀ < 20  83 30 < Dif₅₀ < not tested  84 30 <Dif₅₀ < not tested Sec-1 30 < Dif₅₀ < not tested  93 30 < Dif₅₀ < nottested Sec-3 10 < Dif₅₀ < 15  94 15 < Dif₅₀ < 20  95 15 < Dif₅₀ < 20  9715 < Dif₅₀ < 20 Sec-7 15 < Dif₅₀ < 20  96 10 < Dif₅₀ < 15  98 20 < Dif₅₀< 30  90 15 < Dif₅₀ < 20  91 30 < Dif₅₀ < not tested  92 20 < Dif₅₀ < 30 99 15 < Dif₅₀ < 20 Sec-16 20 < Dif₅₀ < 30 100 15 < Dif₅₀ < 20 Sec-18 &Sec-20 20 < Dif₅₀ < 30 Sec-19 20 < Dif₅₀ < 30 Sec-21 20 < Dif₅₀ < 30Sec-22 15 < Dif₅₀ < 20 Sec-23 NT  85 10 < Dif₅₀ < 15  14 0.5 < Dif₅₀ <0.75  1 100% Death <2.5  2 3.25 < Dif₅₀ < 5 INVS-MG-56B 30 < Dif₅₀ < nottested  4 3 < IC₅₀ < 4 INVS-MG-57A 20 < Dif₅₀ < 30 INVS-MG-58C = 34B 15< Dif₅₀ < 20  5 20 < IC₅₀ < 30  6 15 < IC₅₀ < 20  7 15 < IC₅₀ < 20  8 30< Dif₅₀ < not tested  9 5 < IC₅₀ < 7.5  10 15 < Dif₅₀ < 20  11 0.25 <IC₅₀ < 0.375 INVS-MG-44 15 < Dif₅₀ < 20 INVS-MG-59 15 < Dif₅₀ < 20INVS-MG-60 15 < Dif₅₀ < 20 INVS-MG-66B 10 < IC₅₀ < 7.5  12 10 < Dif₅₀ <15  13 not tested < IC₅₀ < 2.5  77 10 < Dif₅₀ < 15  86 15 < Dif₅₀ < 20INVS-MG-86C 30 < Dif₅₀ < not tested INVS-MG-94-aq 30 < Dif₅₀ < nottested INVS-MG-97-IIB 30 < Dif₅₀ < not tested INVS-MG-98B 10 < Dif₅₀ <15  78 10 < Dif₅₀ < 15 INVS-MG-82-II 0.156 < IC₅₀ < 0.31 INVS-MG-99A =12A 0.156 < IC₅₀ < 0.31 INVS-MG-99B = 52B 0.156 < IC₅₀ < 0.31INVS-MG-99D = 52D 0.31 < IC₅₀ < 0.625 INVS-MG-108-IIB 0.31 < IC₅₀ <0.625  16 1.25 < IC₅₀ < 2.5  17 0.07 < IC₅₀ < 0.156  18 0.07 < IC₅₀ <0.156  19 0.31 < IC₅₀ < 0.625 INVS-MG-110-IIB = IC₅₀ = 1.25 110BINVS-MG-111-IIB = 0.07 < IC₅₀ < 0.156 111B INVS-MG-111-III = 0.07 < IC₅₀< 0.156 111B HCl salt  20 IC₅₀ = 2.5  22 0.31 < IC₅₀ < 0.625  23 1.25 <IC₅₀ < 2.5  24 1.25 < IC₅₀ < 2.5  25 1.25 < IC₅₀ < 2.5  26 0.31 < IC₅₀ <0.625 INVS-MG-111-IVB = 0.07 < IC₅₀ < 0.156 111B INVS-MG-111-V = 0.07 <IC₅₀ < 0.156 111B HCl salt INVS-MG-125- 1.25 < IC₅₀ < 2.5 IIA = 125A  560.625 < IC₅₀ < 1.25 INVS-MG-118-IIB 2.5 < IC₅₀ < 5  27 0.625 < IC₅₀ <1.25  28 0.156 < IC₅₀ < 0.31  29 0.039 < IC₅₀ < 0.078  30 0.31 < IC₅₀ <0.625  31 0.156 < IC₅₀ < 0.31  32 IC₅₀ = 1.25 INVS-MG-133-II 1.25 < IC₅₀< 2.5  33 0.625 < IC₅₀ < 1.25  34 1.25 < IC₅₀ < 2.5  35 0.07 < IC₅₀ <0.156 INVS-MG-145-II 0.625 < IC₅₀ < 1.25  36 0.156 < IC₅₀ < 0.31INVS-MG-146-II 0.31 < IC₅₀ < 0.625  37 5 < IC₅₀ < 10  38 1.25 < IC₅₀ <2.5  39 0.07 < IC₅₀ < 0.156 INVS-MG-119A 0.625 < IC₅₀ < 1.25INVS-MG-144B 0.31 < IC₅₀ < 0.625 INVS-MG-147B 0.625 < IC₅₀ < 1.25INVS-MG-149B′ 1.25 < IC₅₀ < 2.5  57 0.07 < IC₅₀ < 0.156  58 0.07 < IC₅₀< 0.156  42 20/20 at 10uM  43 50/40 at 1.25uM  44 2.5 < IC₅₀ < 5  451.25 < IC₅₀ < 2.5  46 0.31 < IC₅₀ < 0.625  47 0.31 < IC₅₀ < 0.625  480.31 < IC₅₀ < 0.625 INVS-MG-136-IIB 0.156 < IC₅₀ < 0.31 INVS-MG-136-IIINT < IC₅₀ < 0.07  49 0.31 < IC₅₀ < 0.625  50 0.625 < IC₅₀ < 1.25  51 NT< IC₅₀ < 0.07  52 0.07 < IC₅₀ < 0.156  53 0.156 < Dif₅₀ < 0.31  87 15 <Dif₅₀ < 10  88 5 < Dif₅₀ < 7.5 INVS-MG-146-IIIB 0.07 < IC₅₀ < 0.156INVS-MG-146-IV 0.07 < IC₅₀ < 0.156 INVS-MG-152-IIB NT < IC₅₀ < 0.03  62NT < IC₅₀ < 0.03 INVS-MG-157-IIB 0.07 < IC₅₀ < 0.156  57 0.07 < IC₅₀ <0.156 INVS-MG-158-IIB 0.03 < IC₅₀ < 0.07  58 0.07 < IC₅₀ < 0.156INVS-MG-169-IIB 0.156 < IC₅₀ < 0.31  59 0.07 < IC₅₀ < 0.156INVS-MG-170-IIB 0.03 < IC₅₀ < 0.07  60 0.07 < IC₅₀ < 0.156  63 IC₅₀ =0.156  54 IC₅₀ = 0.31  64 0.156 < IC₅₀ < 0.31 101  0.5 ± 0.05 102  0.25± 0.04 103  0.25 ± 0.8 104  4.5 ± 0.05 105  0.07 ± 0.04 106 0.350 ± 0.07107  0.42 ± 0.6 108  0.42 ± 0.03 109  0.42 ± 0.04 110  1.2 ± 0.07 111 0.15 ± 0.03 112  1.15 ± 0.04

Example 2 Identification of Novel Compounds for Inhibiting Cancer CellGrowth

In certain embodiments, securinine and norsecurinine analogues wereadministered to cancerous cells, such as acute myeloblastic leukemiacells (e.g., MOLT3 and OCI-AML3) and growth inhibition was analyzed. Theanalogues were effective in inhibiting myeloid growth in addition topromoting differentiation, and provide for reduced proliferation ofacute myeloblastic leukemia cells (Table 2).

TABLE 2 Analogue MOLT3 IC₅₀ (nM) OCI-AML3 IC₅₀ (nM) INVS-MG-82-II 90 100INVS-MG-99B 80 110 INVS-MG-99D 150 168 17 70 80 18 70 90 22 196 220 26160 195 28 165 200 29 60 80 31 60 75 35 130 110 36 115 105 39 80 70 4090 105 41 150 180 46 145 205 47 150 215 48 >300 >300 INVS-MG-136-III 100115

We claim:
 1. A method of treating a myeloid disorder in a subject,comprising: administering to the subject a therapeutically effectiveamount of at least one securinine or norsecurinine analogue compoundthat is sufficient to induce differentiation of the cell, wherein thecompound has the following formula (I):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; R₂, R₃, R₄, and R₅ are eachindependently hydrogen or substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl,sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl,aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato,carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido,cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and wherein adjacent Rgroups may be linked to form a cyclic or polycyclic ring, wherein thering is a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, ora substituted or unsubstituted heterocyclyl; provided that when x is 1,at least one of R₁, R₂, R₃, R₄, and R₅ is other than hydrogen.
 2. Themethod of claim 1, wherein

represents a double bond.
 3. The method of claim 1 or 2, wherein x is 0.4. The method of claim 3, wherein R₅ is alkoxyalkyl.
 5. The method ofclaim 4, wherein R₂ and R₃ are hydrogen.
 6. The method of claim 1 or 2,wherein x is
 1. 7. The method of claim 6, wherein R₂, R₃, R₄, and R₅ areeach hydrogen.
 8. The method of any one of claims 1-7, wherein R₁ ishalogen or optionally substituted alkyl, aryl, alkenyl, or alkynyl. 9.The method of any one of claims 1-8, wherein R₁ is optionallysubstituted alkenyl.
 10. The method of any one of claims 1-8, wherein R₁is optionally substituted alkynyl.
 11. The method of claim 1, whereinthe securinine or norsecurinine analogue is selected from:

or pharmaceutically acceptable salts thereof.
 12. A method of treating amyeloid disorder in a subject, comprising: administering to the subjecta therapeutically effective amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingformula I′:

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; R₂, R₃, R₄, and R₅ are eachindependently hydrogen or substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkyl alkyl,heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl,sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl,aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato,carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido,cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; wherein adjacent R groupsmay be linked to form a cyclic or polycyclic ring, wherein the ring is asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted cycloalkyl, or a substitutedor unsubstituted heterocyclyl; and wherein R₆ is C₁-C₆ alkyl; providedthat when x is 1, at least one of R₁, R₂, R₃, R₄, and R₅ is other thanhydrogen.
 13. The method of claim 12, wherein

represents a double bond.
 14. The method of claim 12 or 13, wherein x is0.
 15. The method of claim 14, wherein R₅ is alkoxyalkyl.
 16. The methodof claim 15, wherein R₂ and R₃ are hydrogen.
 17. The method of claim 12or 13, wherein x is
 1. 18. The method of claim 17, wherein R₂, R₃, R₄,and R₅ are each hydrogen.
 19. The method of any one of claims 12-18,wherein R₁ is halogen or optionally substituted alkyl, aryl, alkenyl, oralkynyl.
 20. The method of any one of claims 12-19, wherein R₁ isoptionally substituted alkenyl.
 21. The method of any one of claims12-19, wherein R₁ is optionally substituted alkynyl.
 22. The method ofclaim 12, wherein the securinine or norsecurinine analogue is selectedfrom:

and pharmaceutically acceptable salts thereof.
 23. A method of treatinga myeloid disorder in a subject, comprising: administering to thesubject a therapeutically effective amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingFormula (II):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and R₂ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; provided that when x is 1,at least one of R₁ or R₂ is other than hydrogen.
 24. The method of claim23, wherein

represents a double bond.
 25. The method of claim 23 or 24, wherein x is0.
 26. The method of claim 25, wherein R₂ is alkoxyalkyl.
 27. The methodof claim 23 or 24, wherein x is
 1. 28. The method of claim 27, whereinR₂ is hydrogen.
 29. The method of any one of claims 23-28, wherein R₁ isoptionally substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclyl or halogen.
 30. The method of claim23, wherein the securinine or norsecurinine analogue is selected from:

and pharmaceutically acceptable salts thereof.
 31. A method of treatinga myeloid disorder in a subject, comprising: administering to thesubject a therapeutically effective amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the following(III):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond;

represents a double or triple bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and R₂ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl.
 32. The method of claim 31,wherein

represents a double bond.
 33. The method of claim 32, wherein

represents a double bond.
 34. The method of claim 32, wherein

represents a triple bond.
 35. The method of any one of claims 31-34,wherein x is
 0. 36. The method of claim 35, wherein R₂ is alkoxyalkyl.37. The method of any one of claims 31-34, wherein x is
 1. 38. Themethod of claim 37, wherein R₂ is hydrogen.
 39. The method of any one ofclaims 31-38, wherein R₁ is substituted or unsubstituted alkyl, alkenyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, alkaryl, aralkyl, heteroaralkyl, hydroxyl, alkoxy,alkoxyalkyl, alkoxyalkylsilyl, alkoxyalkenyl, aryloxyalkyl, oraminoalkyl.
 40. The method of claim 31, wherein the securinine ornorsecurinine analogue is selected from:

or pharmaceutically acceptable salts thereof.
 41. The method of any oneof claims 1-40, further comprising: administering an anti-proliferativeagent in combination with the securinine or norsecurinine analogue. 42.The method of claim 41, wherein the anti-proliferative agent is ananti-metabolite and/or a nucleoside analogue.
 43. A method of inducingdifferentiation of a cell of the myeloid lineage, comprising:administering to the cell an amount of at least one securinine ornorsecurinine analogue compound with the following formula I:

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; R₂, R₃, R₄, and R₅ are eachindependently hydrogen or substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl,sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl,aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato,carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido,cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and wherein adjacent Rgroups may be linked to form a cyclic or polycyclic ring, wherein thering is a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, ora substituted or unsubstituted heterocyclyl; provided that when x is 1,at least one of R₁, R₂, R₃, R₄, and R₅ is other than hydrogen.
 44. Themethod of claim 43, wherein

represents a double bond.
 45. The method of claim 43 or 44, wherein x is0.
 46. The method of claim 45, wherein R₅ is alkoxyalkyl.
 47. The methodof claim 46, wherein R₂ and R₃ are hydrogen.
 48. The method of claim 43or 44, wherein x is
 1. 49. The method of claim 48, wherein R₂, R₃, R₄,and R₅ are each hydrogen.
 50. The method of any one of claims 43-49,wherein R₁ is halogen or optionally substituted alkyl, aryl, alkenyl, oralkynyl.
 51. The method of any one of claims 43-50, wherein R₁ isoptionally substituted alkenyl.
 52. The method of any one of claims43-50, wherein R₁ is optionally substituted alkynyl.
 53. The method ofclaim 43, wherein the securinine or norsecurinine analogue is selectedfrom:

or pharmaceutically acceptable salts thereof.
 54. A method of inducingdifferentiation of a cell of the myeloid lineage, comprising:administering to the cell an amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingformula I′:

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; R₂, R₃, R₄, and R₅ are eachindependently hydrogen or substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkyl alkyl,heterocyclylalkyl, heteroaralkyl, aralkyl, halo, silyl, hydroxyl,sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl,aryloxy, acyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato,carbamoyl, alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido,cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; wherein adjacent R groupsmay be linked to form a cyclic or polycyclic ring, wherein the ring is asubstituted or unsubstituted aryl, a substituted or unsubstitutedheteroaryl, a substituted or unsubstituted cycloalkyl, or a substitutedor unsubstituted heterocyclyl; and wherein R₆ is C₁-C₆ alkyl; providedthat when x is 1, at least one of R₁, R₂, R₃, R₄, and R₅ is other thanhydrogen.
 55. The method of claim 54, wherein

represents a double bond.
 56. The method of claim 54 or 55, wherein x is0.
 57. The method of claim 56, wherein R₅ is alkoxyalkyl.
 58. The methodof claim 57, wherein R₂ and R₃ are hydrogen.
 59. The method of claim 54or 55, wherein x is
 1. 60. The method of claim 59, wherein R₂, R₃, R₄,and R₅ are each hydrogen.
 61. The method of any one of claims 54-60,wherein R₁ is halogen or optionally substituted alkyl, aryl, alkenyl, oralkynyl.
 62. The method of any one of claims 54-61, wherein R₁ isoptionally substituted alkenyl.
 63. The method of any one of claims54-61, wherein R₁ is optionally substituted alkynyl.
 64. The method ofclaim 54, wherein the securinine or norsecurinine analogue is selectedfrom:

and pharmaceutically acceptable salts thereof.
 65. A method of inducingdifferentiation of a cell of the myeloid lineage, comprising:administering to the cell an amount of at least one securinine ornorsecurinine analogue compound with the following Formula (II):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and R₂ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; provided that when x is 1,at least one of R₁ or R₂ is other than hydrogen.
 66. The method of claim65, wherein

represents a double bond.
 67. The method of claim 65 or 66, wherein x is0.
 68. The method of claim 67, wherein R₂ is alkoxyalkyl.
 69. The methodof claim 65 or 66, wherein x is
 1. 70. The method of claim 69, whereinR₂ is hydrogen.
 71. The method of any one of claims 65-70, wherein R₁ isoptionally substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclyl or halogen.
 72. The method of claim65, wherein the securinine or norsecurinine analogue is selected from:

and pharmaceutically acceptable salts thereof.
 73. A method of inducingdifferentiation of a cell of the myeloid lineage, comprising:administering to the cell an amount of at least one securinine ornorsecurinine analogue compound with the following Formula (III):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond;

represents a double or triple bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and R₂ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl.
 74. The method of claim 73,wherein

represents a double bond.
 75. The method of claim 74, wherein

represents a double bond.
 76. The method of claim 74, wherein

represents a triple bond.
 77. The method of any one of claims 73-76,wherein x is
 0. 78. The method of claim 77, wherein R₂ is alkoxyalkyl.79. The method of any one of claims 73-76, wherein x is
 1. 80. Themethod of claim 79, wherein R₂ is hydrogen.
 81. The method of any one ofclaims 73-80, wherein R₁ is substituted or unsubstituted alkyl, alkenyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, alkaryl, aralkyl, heteroaralkyl, hydroxyl, alkoxy,alkoxyalkyl, alkoxyalkylsilyl, alkoxyalkenyl, aryloxyalkyl, oraminoalkyl.
 82. The method of claim 73, wherein the securinine ornorsecurinine analogue is selected from:

or pharmaceutically acceptable salts thereof.
 83. The method of any oneof claims 43-83, further comprising: administering an anti-proliferativeagent in combination with the securinine or norsecurinine analogue. 84.The method of claim 83, wherein the anti-proliferative agent is ananti-metabolite and/or a nucleoside analogue.
 85. A method of treating amyeloid disorder in a subject, comprising: administering to the subjecta therapeutically effective amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingformula (IV):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; and R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; provided that wherein R₁ issubstituted or unsubstituted heterocyclyl, x is 1, and

represents a single bond, R₁ is not mono-fluoro substituted pyrrolidine;provided that wherein R₁ is substituted or unsubstitutedheteroarylalkylamino, x is 1, and

represents a single bond, R₁ is not indolealkylamino; provided thatwherein R₁ is substituted or unsubstituted arylsulfanyl, x is 1, and

represents a single bond, R₁ is not phenylsulfanyl; and provided thatwherein R₁ is alkylsulfanyl, x is 1, and

represents a single bond R₁ is not propylsulfanyl.
 86. The method ofclaim 85, wherein

represents a single bond.
 87. The method of claim 85 or 86, wherein xis
 1. 88. The method of any one of claims 85-87, wherein R₁ is hydrogenor substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino, aminoalkyl,imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl,amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl,alkylsulfinyl, arylsulfinyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphino, thioalkyl, or thioaryl.
 89. The methodof claim 85, wherein the securinine or norsecurinine analogue isselected from:

or pharmaceutically acceptable salts thereof.
 90. A method of treating amyeloid disorder in a subject, comprising: administering to the subjecta therapeutically effective amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingformula (IV′):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and wherein R₂ is C₁-C₆alkyl; provided that wherein R₁ is substituted or unsubstitutedheterocyclyl, R₁ is not mono-fluoro substituted pyrrolidine, x is 1, and

represents a single bond; provided that wherein R₁ is substituted orunsubstituted heteroarylalkylamino, R₁ is not indolealkylamino, x is 1,and

represents a single bond; provided that wherein R₁ is substituted orunsubstituted arylsulfanyl, R₁ is not phenylsulfanyl, x is 1, and

represents a single bond; and provided that wherein R₁ is alkylsulfanyl,R₁ is not propylsulfanyl, x is 1, and

represents a single bond.
 91. The method of claim 90, wherein

represents a single bond.
 92. The method of claim 90 or 91, wherein xis
 1. 93. The method of any one of claims 90-92, wherein R₁ is hydrogenor substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino, aminoalkyl,imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl,amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl,alkylsulfinyl, arylsulfinyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphino, thioalkyl, or thioaryl.
 94. The methodof any one of claims 85-93, further comprising: administering ananti-proliferative agent in combination with the securinine analogue.95. The method of claim 94, wherein the anti-proliferative agent is ananti-metabolite and/or a nucleoside analogue.
 96. A method of inducingdifferentiation of a cell of the myeloid lineage, comprising:administering to the cell an amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingformula (IV):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; and R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; provided that wherein R₁ issubstituted or unsubstituted heterocyclyl, R₁ is not mono-fluorosubstituted pyrrolidine, x is 1, and

represents a single bond; provided that wherein R₁ is substituted orunsubstituted heteroarylalkylamino, R₁ is not indolealkylamino, x is 1,and

represents a single bond; provided that wherein R₁ is substituted orunsubstituted arylsulfanyl, R₁ is not phenylsulfanyl, x is 1, and

represents a single bond; and provided that wherein R₁ is alkylsulfanyl,R₁ is not propylsulfanyl, x is 1, and

represents a single bond.
 97. The method of claim 96, wherein

represents a single bond.
 98. The method of claim 96 or 97, wherein xis
 1. 99. The method of any one of claims 96-98, wherein R₁ is hydrogenor substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino, aminoalkyl,imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl,amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl,alkylsulfinyl, arylsulfinyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphino, thioalkyl, or thioaryl.
 100. The methodof claim 96, wherein the securinine or norsecurinine analogue isselected from:

or pharmaceutically acceptable salts thereof.
 101. A method of inducingdifferentiation of a cell of the myeloid lineage, comprising:administering to the cell an amount of at least one securinine ornorsecurinine analogue compound that is sufficient to inducedifferentiation of the cell, wherein the compound has the followingformula (IV′):

or pharmaceutically acceptable salts thereof, wherein as valence andstability permit:

represents a single or double bond; x is 0 or 1; R₁ is hydrogen orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino,heteroarylalkylamino, aminoalkyl, imino, nitro, nitroso, sulfo,sulfonato, alkylsulfanyl, arylsulfanyl, cycloalkylsulfanyl,heterocyclylsulfanyl, heteroarylsulfanyl, amidoalkylsulfanyl,arylalkysulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, arylsulfinyl,alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato,phospho, phosphino, thioalkyl, or thioaryl; and wherein R₂ is C₁-C₆alkyl; provided that wherein R₁ is substituted or unsubstitutedheterocyclyl, R₁ is not mono-fluoro substituted pyrrolidine, x is 1, and

represents a single bond; provided that wherein R₁ is substituted orunsubstituted heteroarylalkylamino, R₁ is not indolealkylamino, x is 1,and

represents a single bond; provided that wherein R₁ is substituted orunsubstituted arylsulfanyl, R₁ is not phenylsulfanyl, x is 1, and

represents a single bond; and provided that wherein R₁ is alkylsulfanyl,R₁ is not propylsulfanyl, x is 1, and

represents a single bond.
 102. The method of claim 101, wherein

represents a single bond.
 103. The method of claim 101 or 102, wherein xis
 1. 104. The method of any one of claims 101-103, wherein R₁ ishydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,heteroaralkyl, aralkyl, halo, silyl, hydroxyl, sulfhydryl, alkoxy,alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, aryloxy, acyl,alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl,alkylcarbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano,isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl,thioformyl, amino, alkylamino, arylamino, cycloalkylamino,heterocyclylamino, cycloalkylalkylamino, arylalkylamino, aminoalkyl,imino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl,cycloalkylsulfanyl, heterocyclylsulfanyl, heteroarylsulfanyl,amidoalkylsulfanyl, arylalkysulfanyl, heteroarylalkylsulfanyl,alkylsulfinyl, arylsulfinyl, arylsulfonyl, phosphono, phosphonato,phosphinato, phospho, phosphino, thioalkyl, or thioaryl.
 105. The methodof any one of claims 96-104, further comprising: administering ananti-proliferative agent in combination with the securinine analogue.106. The method of claim 105, wherein the anti-proliferative agent is ananti-metabolite and/or a nucleoside analogue.
 107. The method of any oneof claim 43-84 or 96-106, wherein the cell is in a subject.
 108. Themethod of any one of claim 1-42, 85-95 or 107, wherein the subject is amammal.
 109. The method of claim 108, wherein the mammal is a human.110. The method of any one of claim 43-84 or 96-106, wherein the cell isa common myeloid progenitor cell.
 111. The method of any one of claim43-84 or 96-106, wherein the cell is a myeloblast.
 112. The method ofany one of claim 43-84 or 96-106, wherein the cell is a megakaryoblast.113. The method of any one of claim 43-84 or 96-106, wherein the cell isa proerythroblast.
 114. The method of any one of claim 43-84 or 96-106,wherein the cell is a monoblast.
 115. The method of any one of claim43-84 or 96-106, wherein the cell is a promegakaryocyte, megakaryocyte,basophilic erythroblast, polychromatic erythroblast, orthochromaticerythroblast (normoblast), polychromatic erythrocyte, promonocyte,monocyte, or any one of a basophilic/neutrophilic/eosinophilic precursorcells.
 116. The method of any one of claim 43-84, 96-106 or 107, whereinthe cell is a cancer cell.
 117. The method of claim 116, wherein thecell is a leukemic cell.
 118. The method of claim 116, wherein the cellis a sarcoma cell.
 119. The method of any one of claims 41, 83, 94 and105, wherein the anti-proliferative agent is an alkylating agent. 120.The method of any one of claims 41, 83, 94 and 105, wherein theanti-proliferative agent is an antibiotic-type agent.
 121. The method ofany one of claims 41, 83, 94 and 105, wherein the anti-proliferativeagent is an hormonal anticancer agent.
 122. The method of any one ofclaims 41, 83, 94 and 105, wherein the anti-proliferative agent is animmunological agent.
 123. The method of any one of claims 41, 83, 94 and105, wherein the anti-proliferative agent is an interferon-type agent.124. The method of any one of claims 41, 83, 94 and 105, wherein theanti-proliferative agent is an antineoplastic agent.
 125. The method ofany one of claim 1-42 or 85-95, wherein the myeloid disorder isassociated with increased proliferation of cells of the myeloid lineage.126. The method of claim 125, wherein the myeloid disorder is leukemia.127. The method of claim 125, wherein the myeloid disorder is a sarcoma.128. The method of any one of claims 125-127, wherein the increasedproliferation of the cells is reduced following administration of thesecurinine or norsecurinine analogue.
 129. The method of any one ofclaim 1-42 or 85-95, wherein the myeloid disorder is associated withreduced differentiation and/or survival of a myeloid cell or a cell ofmyeloid lineage.
 130. The method of any one of claim 1-42 or 85-95,wherein the myeloid disorder is associated with reduced hematopoiesis ofcells of the myeloid lineage.
 131. The method of any one of claim 1-42or 85-95, wherein the myeloid disorder is an autoimmune disease. 132.The method of any one of claim 1-42 or 85-95, wherein myeloid disorderis selected from the group consisting of: acute myeloid leukemia (AML),chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS),myelodysplasia, Myelodysplastic Syndrome (e.g., refractory anemia (RA),refractory anemia with ring sideroblasts (RARS), refractory anemia withexcess blasts (RAEB), refractory anemia with excess blasts intransformation (RAEBT), and/or chronic myelomonocytic leukemia (CMMoL)),myeloid sarcoma, chloroma, chronic myeloproliferative diseases (CMPD),essential thrombocythemia, polycythemia vera, chronic myelogenousleukemia, myelofibrosis, myelofibrosis with myeloid metaplasia (MMM—alsoknown as agnogenic myeloid metaplasia or idiopathic myelofibrosis),atypical CMD, chronic neutrophilic leukemia, chronic eosinophilicleukemia, systemic mastocytosis, mast cell disease, chronic neutrophilicleukemia (CNL), chronic eosinophilic leukemia (CEL), hypereosinophilicsyndrome (HES), unclassified MPD (UMPD), chronic myelomonocytic leukemia(CMML), juvenile myelomonocytic leukemia (JMML), Down Syndrome relatedmyeloid disorders, and myeloid processes that display overlappingfeatures of MDS and CMPD (hybrid CMD).
 133. The method of any one ofclaim 1-42 or 85-95, wherein the subject having the myeloid disorder hasa mutation in one or more of the following genes: JAK2, NPM1, MPL, RAS,RUNX1, ASXL1, BCORL1, CBL, DNMT3A, EZH2, IDH1/IDH2, TET2, UTX, SF3B1,SRSF2, U2AF35/U2AF1, ZRSR2, PTPN11, SH3KBP1, CDKN2A/B, TRIM33, CTNNA1,SOCS1 and/or SF3B1.